Substituted nucleosides, nucleotides and analogs thereof

ABSTRACT

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57.

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEQLISTING_065C5—Substitute, created Sep. 6, 2016, which is 1 Kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

BACKGROUND

Field

The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are nucleotide analogs, pharmaceutical compositions that include one or more nucleotide analogs and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a nucleotide analog, alone or in combination therapy with one or more other agents.

Description

Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-metabolites, which, in turn, may inhibit polymerases involved in viral or cell proliferation. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a method of ameliorating and/or treating a hepatitis C viral (HCV) infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a HCV infection. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection.

Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, in the manufacture of a medicament for inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include administering to a subject identified as suffering from a HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, another antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable salt thereof, selected from Compound 1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 6001-6078, 7000-7027 and 8000-8016, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the method can include administering a second agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example HCV protease inhibitors.

FIG. 2 shows example nucleoside HCV polymerase inhibitors.

FIG. 3 shows example non-nucleoside HCV polymerase inhibitors.

FIG. 4 shows example NS5A inhibitors.

FIG. 5 shows example other antivirals.

FIG. 6 shows example compounds of Formula (CC) and alpha-thiotriphosphates thereof, wherein Formula (CC) and alpha-thiotriphosphates thereof are described herein.

FIG. 7 shows example compounds of Formula (AA), wherein Formula (AA) is described herein.

FIG. 8 shows example compounds of Formula (BB), wherein Formula (BB) is described herein.

FIG. 9 shows example compounds of Formula (I), wherein Formula (I) is described herein.

FIG. 10 shows the gels from the assessment of incorporation of several compound with a uracil base by the human mitochondrial RNA polymerase.

FIG. 11 shows the gels from the assessment of incorporation of several compounds with a guanine base by the human mitochondrial RNA polymerase.

FIGS. 12A-D shows the results of the inhibition of mitochondrial protein synthesis assays.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), R^(6D), R^(6E), R^(6F), R^(6G), R^(6H), R^(7A), R^(7B), R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R^(A1), R^(A2), R^(A3) and R^(A4) represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined previously.

Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl and (1,3-thiazinan-4-yl)methyl.

“Lower alkylene groups” are straight-chained —CH₂— tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene (—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an —O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein each X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—” group wherein each X is a halogen, and R_(A) is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in which R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which R and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in which R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which R and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group in which R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in which R and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substituted or unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “C₁-C₃ alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).

The term “nucleoside” is used herein in its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a N-glycosidic bond, such as attached via the 9-position of a purine-base or the 1-position of a pyrimidine-base. Examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety. A modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom. A “nucleoside” is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.

The term “nucleotide” is used herein in its ordinary sense as understood by those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5′-position.

As used herein, the term “heterocyclic base” refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine-base and an optionally substituted triazole-base (for example, a 1,2,4-triazole). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “pyrimidine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, uric acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). An example of an optionally substituted triazole-base is 1,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g., 8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Pat. Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases. In some embodiments, a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).

The term “—N-linked amino acid” refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group. When the amino acid is attached in an —N-linked amino acid, one of the hydrogens that is part of the main-chain amino or mono-substituted amino group is not present and the amino acid is attached via the nitrogen. N-linked amino acids can be substituted or unsubstituted.

The term “—N-linked amino acid ester derivative” refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group. In some embodiments, the ester group has a formula selected from alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— and aryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups include substituted and unsubstituted versions of the following: methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—, n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—, neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—, cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—, benzyl-O—C(═O)— and naphthyl-O—C(═O)—. N-linked amino acid ester derivatives can be substituted or unsubstituted.

The term “—O-linked amino acid” refers to an amino acid that is attached to the indicated moiety via the hydroxy from its main-chain carboxylic acid group. When the amino acid is attached in an —O-linked amino acid, the hydrogen that is part of the hydroxy from its main-chain carboxylic acid group is not present and the amino acid is attached via the oxygen. O-linked amino acids can be substituted or unsubstituted.

As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.

The terms “phosphorothioate” and “phosphothioate” refer to a compound of the general formula

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and “triphosphate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms.

The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); 4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of a phosphate and a phosphorothioate groups are intended to be included. Examples of tautomers of a phosphorothioate include the following:

Furthermore, all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.

It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).

It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein: B¹ can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

R¹ can be selected from an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆ cycloalkyl; each ------- can be absent or a single bond, provided that both -------- are each absent or both -------- are each a single bond; when both ------ are each a single bond, then R² can be halo, N₃, —OR^(7A) or —N(R^(7B)R^(7C)); R⁴ can be absent; R³ can be oxygen (O); and R^(p) can be

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selected from O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl.

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; when both ------ are each absent, then R^(p) can be absent; R² can be halo, N₃, —OR^(7A) or —N(R^(7B)R^(7C)); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be each an oxygen atom which are linked together by a carbonyl group; and R⁴ can be hydrogen or

R^(5A) can be selected from O⁻, OH, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,

R^(5B) can be selected from O⁻, OH, an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, an —O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,

R^(6A) can be an optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl; R^(6B) and R^(6C) can be independently selected from hydrogen, an unsubstituted C₁₋₆ alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl and an unsubstituted C₃₋₆ cycloalkyl; R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen or NHR^(6H); R^(6F) can be NHR^(6I); R^(6G) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2); R^(6H) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4); R^(6I) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A5) and —C(═O)OR^(A6); X¹ can be N (nitrogen) or —CR^(6J), R^(6J) can be selected from hydrogen, halogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) can be independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl, aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl); R^(7A) can be hydrogen or —C(═O)R¹²; R^(7B) and R^(7C) can be independently hydrogen or an optionally substituted C₁₋₆ alkyl; R⁸ and R¹² can be independently an optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl; R⁹, R¹⁰ and R¹¹ can be independently absent or hydrogen; R^(8A), R^(9A), R^(11A), R^(12A), R^(8B), R^(9B), R^(11B), R^(12B), R^(p2), R^(p3), R^(p5) and R^(p6) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; R^(10A), R^(10B), R^(13A), R^(13B), R^(p4) and R^(p7) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; R^(14A), R^(14B), R^(15A), R^(15B), R^(p8) and R^(p9) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; n can be 0 or 1; p, q, and r can be independently 1 or 2; s, t and u can be independently 3, 4 or 5; Z¹, Z^(1A), Z^(1B) and Z^(p1) can be independently O (oxygen) or S (sulfur); and provided that when R⁴ is

and R^(5A) is O⁻ or OH, then R^(5B) is O⁻, OH,

an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

The substituents attached to the 2′-carbon can vary. In some embodiments, R² can be halo. For example, R² can be fluoro or chloro. In other embodiments, R² can be N₃. In some embodiments, R² can be —OH. In other embodiments, R² can be OR^(7A), wherein R^(7A) can be —C(═O)R¹², and R¹² can be an optionally substituted C₁₋₆ alkyl. Suitable alkyl groups include, but are not limited to optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In yet still other embodiments, R² can be OR^(7A), wherein R^(7A) can be —C(═O)R¹², and R¹² can be an optionally substituted C₃₋₆ cycloalkyl. Suitable cycloalkyl groups include, but are not limited to optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiment, R² can be —N(R^(7B)R^(7C)), wherein R^(7B) and R^(7C) can be independently hydrogen or an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(7B) and R^(7C) can be both hydrogen, such that R² can be —NH₂. In other embodiments, at least one of R^(7B) and R^(7C) can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(7B) and R^(7C) can be both an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(7B) and R^(7C) can be the same. In other embodiments, R^(7B) and R^(7C) can be different.

Various substituents can be attached to the 3′-carbon of the pentose ring. In some embodiments, R³ can be —OH. In other embodiments, R³ can be —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₁₋₆ alkyl such as those described herein. In still other embodiments, R³ can be —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₃₋₆ cycloalkyl. Examples of suitable optionally substituted C₃₋₆ cycloalkyl groups are described herein.

In some embodiments, R² and R³ can each be an oxygen atom and the oxygen atoms can be linked together by a carbonyl group. In other embodiments, R² and R³ can be both —OH. In other embodiments, R² can be halo and R³ can be —OH. In still other embodiments, R² can be halo and R³ can be —OC(═O)R⁸.

In some embodiments, R¹ can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R¹ can be an unsubstituted C₁₋₆ alkyl. For example, R¹ can be unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstituted isobutyl, unsubstituted tert-butyl, unsubstituted pentyl (branched and straight-chained) or unsubstituted hexyl (branched and straight-chained). In some embodiments, R¹ can be a substituted C₁₋₆ alkyl. Suitable substitutions are described herein. As an example, R¹ can be a halo-substituted C₁₋₆ alkyl (such as —CF₃ or —CH₂CH₂F). In other embodiments, R¹ can be an optionally substituted C₂₋₆ alkenyl. Suitable alkenyl groups include, but are not limited to optionally substituted variants of the following: ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, pentenyl (branched and straight-chained), hexenyl (branched and straight-chained), vinyl and alkenyl. In still other embodiments, R¹ can be an optionally substituted C₂₋₆ alkynyl. In yet still other embodiments, R¹ can be an optionally substituted C₃₋₆ cycloalkyl, such as those described herein.

In some embodiments, both ------ can be each absent, R^(p) can be absent; R² can be halo, N₃, —OR^(7A) or —N(R^(7B)R^(7C)); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be each an oxygen atom which are linked together by a carbonyl group; and R⁴ can be hydrogen or

When both ------ are absent, Formula (I) can have the structure:

In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴ can be

In some embodiments, the compound of Formula (I) can be a monophosphate. In other embodiments, the compound of Formula (I) can be a thiomonophosphate. In some embodiments, the compound of Formula (I) can be a diphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiodiphosphate. In some embodiments, the compound of Formula (I) can be a triphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiotriphosphate. In some embodiments, R⁴ can be

R^(5A) can be O⁻ or OH; and R^(5B) can be O⁻ or OH. In other embodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 0. In still other embodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 1. The substituents attached to the phosphorus can vary. In some embodiments, a compound of Formula (I) can be a phosphoroamidate. In other embodiments, a compound of Formula (I) can be a thiophosphoroamidate. In still other embodiments, a compound of Formula (I) can be a phosphorbisamidate. In yet still other embodiments, a compound of Formula (I) can be a thiophosphorbisamidate.

In some embodiments, R^(5A) can be an optionally substituted N-linked amino acid. Various amino acids are suitable, including those described herein. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. In other embodiments, R^(5A) can be an optionally substituted N-linked amino acid ester derivative. Examples of N-linked amino acid ester derivatives include, but are not limited to, ester derivatives of any of the following amino acids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of N-linked amino acid ester derivatives include, but are not limited to, an ester derivative of any of the following amino acids: alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. In some embodiments, the N-linked amino acid ester derivative can be a C₁₋₆ alkyl ester derivative, for example, an isopropyl ester of alanine. In other embodiments, the N-linked amino acid ester derivative can be a C₃₋₆ cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.

In some embodiments, R^(5A) can have the structure

wherein R¹³ can be selected from hydrogen, an optionally substituted C₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and an optionally substituted haloalkyl; R¹⁴ can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆ alkyl); and R¹⁵ can be hydrogen or an optionally substituted C₁₋₄-alkyl; or R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁴ is substituted, R¹⁴ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁴ can be an unsubstituted C₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁴ can be hydrogen. In other embodiments, R¹⁴ can be methyl. In some embodiments, R¹³ can be an optionally substituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹³ can be methyl or isopropyl. In some embodiments, R¹³ can be ethyl or neopentyl. In other embodiments, R¹³ can be an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹³ can be an optionally substituted cyclohexyl. In still other embodiments, R¹³ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹³ can be an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments, R¹³ can be an optionally substituted benzyl. In some embodiments, R¹³ can be an optionally substituted C₁₋₆ haloalkyl, for example, CF₃. In some embodiments, R¹⁵ can be hydrogen. In other embodiments, R¹⁵ can be an optionally substituted C₁₋₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R¹⁵ can be methyl. In some embodiments, R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁴ and R¹⁵, the carbon to which R¹⁴ and R¹⁵ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁴ and R¹⁵ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁴ and R¹⁵ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(5B) can be an —O-optionally substituted aryl. For example, R^(5B) can be an —O-optionally substituted phenyl. When the phenyl is substituted, the ring can be substituted 1, 2, 3 or more than 3 times. Suitable mono-substituted phenyl groups include, ortho-substituted phenyl, meta-substituted phenyl and para-substituted phenyl. In other embodiments, R^(5B) can be an —O-unsubstituted aryl. Alternatively, R^(5B) can be an —O-optionally substituted naphthyl. In other embodiments, R^(5B) can be an —O-optionally substituted heteroaryl. For example, R^(5B) can be an —O-optionally substituted quinolinyl. In still other embodiments, R^(5B) can be an —O-optionally substituted heterocyclyl.

In some embodiments, R^(5B) is an optionally substituted N-linked amino acid, such as those described for R^(5A). In other embodiments, R^(5B) is an optionally substituted N-linked amino acid ester derivative, for example, those described herein. In some embodiments, R^(5B) can have the structure

wherein R¹⁶ can be selected from hydrogen, an optionally substituted C₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and an optionally substituted haloalkyl; R¹⁷ can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆ alkyl); and R¹⁸ can be hydrogen or an optionally substituted C₁₋₄-alkyl; or R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁷ is substituted, R¹⁷ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁷ can be an unsubstituted C₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁷ can be hydrogen. In other embodiments, R¹⁷ can be methyl. In some embodiments, R¹⁶ can be an optionally substituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹⁶ can be methyl or isopropyl. In some embodiments, R¹⁶ can be ethyl or neopentyl. In other embodiments, R¹⁶ can be an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹⁶ can be an optionally substituted cyclohexyl. In still other embodiments, R¹⁶ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹⁶ can be an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments, R¹⁶ can be an optionally substituted benzyl. In some embodiments, R¹⁶ can be an optionally substituted C₁₋₆ haloalkyl, for example, CF₃. In some embodiments, R¹⁶ can be hydrogen. In other embodiments, R¹⁸ can be an optionally substituted C₁₋₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R¹⁸ can be methyl. In some embodiments, R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁷ and R¹⁸, the carbon to which R¹⁷ and R¹⁸ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁷ and R¹⁸ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁷ and R¹⁸ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(5A) can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^(5B) can be an —O-optionally substituted aryl. In other embodiments, R^(5A) can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^(5B) can be an —O-optionally substituted heteroaryl. In some embodiments, R^(5A) can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^(5A) can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

In some embodiments, R^(5A) can be

When R^(5A) is

R^(8A) and R^(9A) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; and R^(10A) can be selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(8A) and R^(9A) can be hydrogen. In other embodiments, at least one of R^(8A) and R^(9A) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(10A) can be hydrogen. In other embodiments, R^(10A) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(10A) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments, R^(10A) can be an optionally substituted aryl. In yet still other embodiments, R^(10A) can be —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(10A) can be an unsubstituted —O—C₁₋₄ alkyl.

In some embodiments, R^(5B) can be

When R^(5B) is

R^(8B) and R^(9B) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; and R^(10B) can be selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(8B) and R^(9B) can be hydrogen. In other embodiments, at least one of R^(8B) and R^(9B) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(10B) can be hydrogen. In other embodiments, R^(10B) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(10B) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments, R^(10B) can be an optionally substituted aryl. In yet still other embodiments, R^(10B) can be —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments. R^(10B) can be an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

wherein R^(11A) and R^(12A) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; R^(13A) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; and Z^(1A) can be independently O (oxygen) or S (sulfur). In some embodiments, R^(11A) and R^(12A) can be hydrogen. In other embodiments, at least one of R^(11A) and R^(12A) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(13A) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(13A) can be an unsubstituted C₁₋₄ alkyl. In other embodiments, R^(13A) can be an optionally substituted aryl. In still other embodiments, R^(13A) can be an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(13A) can be an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, Z^(1A) can be O (oxygen). In other embodiments, Z^(1A) can be or S (sulfur).

In some embodiments, R^(5B) can be

wherein R^(11B) and R^(12B) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; R^(13B) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; and Z^(1B) can be independently O (oxygen) or S (sulfur). In some embodiments, R^(11B) and R^(12B) can be hydrogen. In other embodiments, at least one of R^(11B) and R^(12B) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(13B) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(13B) can be an unsubstituted C₁₋₄ alkyl. In other embodiments, R^(13B) can be an optionally substituted aryl. In still other embodiments, R^(13B) can be an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(13B) can be an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, Z^(1B) can be O (oxygen). In other embodiments, Z^(1B) can be or S (sulfur). In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(14A) can be hydrogen. In other embodiments, R^(14A) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(14A) can be an optionally substituted aryl. In some embodiments, R^(14A) can be a C₁₋₆ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, p can be 1. In other embodiments, p can be 2.

In some embodiments, R^(5B) can be

In some embodiments, R^(14B) can be hydrogen. In other embodiments, R^(14B) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(14B) can be an optionally substituted aryl. In some embodiments, R^(14B) can be a C₁₋₆ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, q can be 1. In other embodiments, q can be 2. In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(15A) can be hydrogen. In other embodiments, R^(15A) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(15A) can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^(15A) can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(15A) can be an unsubstituted C₁₋₆ alkyl. In some embodiments, s can be 3. In other embodiments, s can be 4. In still other embodiments, s can be 5.

In some embodiments, R^(5B) can be

In some embodiments, R^(15B) can be hydrogen. In other embodiments, R^(15B) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(15B) can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^(15B) can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(15B) can be an unsubstituted C₁₋₆ alkyl. In some embodiments, t can be 3. In other embodiments, t can be 4. In still other embodiments, t can be 5. In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) and/or R^(5B) can be isopropyloxycarbonyloxymethoxy (POC) group. In some embodiments, R^(5A) and/or R^(5B) can be pivaloyloxymethoxy (POM) group. In some embodiments, R^(5A) and R^(5B) can be both a isopropyloxycarbonyloxymethoxy (POC) group, and form a bis(isopropyloxycarbonyloxymethoxy) (bis(POC)) prodrug. In other embodiments, R^(5A) and R^(5B) can be both a pivaloyloxymethoxy (POM) group, and form a bis(pivaloyloxymethoxy) (bis(POM)) prodrug. In still other embodiments, R^(5A) and R^(5B) can be both a S-acylthioethyl (SATE)-O— group and form a SATE ester prodrug. In some embodiments, R^(5A) and R^(5B) can be the same. In other embodiments, R^(5A) and R^(5B) can be different.

In some embodiments, both -------- can be each a single bond; R⁴ can be absent; R³ can be oxygen (O); and R^(p) can be

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selected from O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl.

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative. When both ------ are each a single bond, Formula (I) can have the structure:

In some embodiments, R^(p1) can be O⁻. In other embodiments, R^(p1) can be OH. In other embodiments, R^(p1) can be an —O-optionally substituted C₁₋₆ alkyl. For example, R^(p1) can be a substituted or an unsubstituted version of the following: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straight chained) and hexoxy (branched or straight chained).

In some embodiments, R^(p1) can be

wherein R^(p2) and R^(p3) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; and R^(p4) can be selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(p2) and R^(p3) can be hydrogen. In other embodiments, at least one of R^(p2) and R^(p3) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(p4) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(p4) can be an unsubstituted C₁₋₄ alkyl. In other embodiments, R^(p4) can be an optionally substituted aryl. In still other embodiments, R^(p4) can be an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(p4) can be an unsubstituted —O—C₁₋₄ alkyl.

In some embodiments, R^(p1) can be

wherein R^(p5) and R^(p6) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl; R^(p7) can be independently selected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; and Z^(p1) can be independently O (oxygen) or S (sulfur). In some embodiments, R^(p5) and R^(p6) can be hydrogen. In other embodiments, at least one of R^(p5) and R^(p6) can be an optionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments, R^(p7) can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments, R^(p7) can be an unsubstituted C₁₋₄ alkyl. In other embodiments, R^(p7) can be an optionally substituted aryl. In still other embodiments, R^(p7) can be an optionally substituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^(p7) can be an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, Z^(p1) can be O (oxygen). In other embodiments, Z^(p1) can be or S (sulfur). In some embodiments, R^(p1) can be isopropyloxycarbonyloxymethyloxy (POC) group. In some embodiments, R^(p1) can be pivaloyloxymethyloxy (POM) group.

In some embodiments, R^(p1) can be

In some embodiments, R^(p8) can be hydrogen. In other embodiments, R^(p8) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(p8) can be an optionally substituted aryl. In some embodiments, R^(p8) can be a C₁₋₆ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, r can be 1. In other embodiments, r can be 2.

In some embodiments, R^(p1) can be

In some embodiments, R^(p9) can be hydrogen. In other embodiments, R^(p9) can be an optionally substituted C₁₋₂₄ alkyl. In still other embodiments, R^(p9) can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^(p9) can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(p9) can be an unsubstituted C₁₋₆ alkyl. In some embodiments, u can be 3. In other embodiments, u can be 4. In still other embodiments, u can be 5. In some embodiments, R^(p1) can be a S-acylthioethyl (SATE) group and form a SATE ester prodrug.

In some embodiments, R^(p1) can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. For example, R^(p1) can be optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof. In some embodiments, R^(p1) can be selected from N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester and N-leucine isopropyl ester. In some embodiments, R^(p1) can have the structure

wherein R^(p10) can be selected from hydrogen, an optionally substituted C₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and an optionally substituted haloalkyl; R^(p11) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆ alkyl); and R^(p12) can be hydrogen or an optionally substituted C₁₋₄-alkyl; or R^(p11) and R^(p12) can be taken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R^(p11) is substituted, R^(p11) can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^(p11) can be an unsubstituted C₁₋₆-alkyl, such as those described herein. In some embodiments, R^(p11) can be hydrogen. In other embodiments, R^(p11) can be methyl. In some embodiments, R^(p10) can be an optionally substituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R^(p10) can be methyl or isopropyl. In some embodiments, R^(p10) can be ethyl or neopentyl. In other embodiments, R^(p10) can be an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R^(p10) can be an optionally substituted cyclohexyl. In still other embodiments, R^(p10) can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^(p10) can be an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments, R^(p10) can be an optionally substituted benzyl. In some embodiments, R^(p10) can be an optionally substituted C₁₋₆ haloalkyl, for example, CF₃. In some embodiments, R^(p12) can be hydrogen. In other embodiments, R^(p12) can be an optionally substituted C₁₋₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In some embodiments, R^(p12) can be methyl. In some embodiments, R^(p11) and R^(p12) can be taken together to form an optionally substituted C₃₋₆ cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^(p11) and R^(p12), the carbon to which R^(p11) and R^(p12) are attached may be a chiral center. In some embodiment, the carbon to which R^(p11) and R^(p12) are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^(p11) and R^(p12) are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

The nucleobase can vary. In some embodiments, B¹ can be uracil. In some embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In other embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In some embodiments, R^(6A) can be an optionally substituted C₁₋₆ alkyl. For example, R^(6A) can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In other embodiments, R^(6A) can be an optionally substituted C₃₋₆ cycloalkyl, for example, optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be guanine. In some embodiments, B¹ can be an optionally substituted

In other embodiments, B¹ can be an optionally substituted

wherein R^(6B) can be selected from hydrogen, an unsubstituted C₁₋₆ alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl and an unsubstituted C₃₋₆ cyclo alkyl. In some embodiments, B¹ can be unsubstituted

In some embodiments, R^(6B) can be an unsubstituted C₁₋₆ alkyl. For example, R^(6B) can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In some embodiments, R^(6B) can be an unsubstituted C₃₋₆ alkenyl. In other embodiments, R^(6B) can be an unsubstituted C₃₋₆ alkynyl. In still other embodiments, R^(6B) can be an unsubstituted C₃₋₆ cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be an optionally substituted

wherein R^(6C) can be selected from hydrogen, an unsubstituted C₁₋₆ alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl and an unsubstituted C₃₋₆ cycloalkyl. In some embodiments, B¹ can be unsubstituted

In some embodiments, R^(6C) can be hydrogen. In some embodiments, R^(6C) can be an unsubstituted C₁₋₆ alkyl. For example, R^(6C) can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In some embodiments, R^(6C) can be an ethyl. In some embodiments, R^(6C) can be an unsubstituted C₃₋₆ alkenyl. In other embodiments, R^(6C) can be an unsubstituted C₃₋₆ alkynyl. In other embodiments, R^(6C) can be an unsubstituted C₃₋₆ cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be adenine. In some embodiments, B¹ can be an optionally substituted

wherein X¹ can be N (nitrogen) or —CR^(6J); R^(6J) can be selected from hydrogen, halogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen or NHR^(6H); R^(6G) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2); R^(6H) can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4); R^(A1), R^(A2), R^(A3) and R^(A4) can be independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl, aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl). In some embodiments, X¹ can be N (nitrogen). In other embodiments, X¹ can be —CR^(6I), wherein CR^(6I) can be selected from hydrogen, halogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl. In some embodiments, X¹ can be CH. In some embodiments, R^(6D) and R^(6E) can be both NH₂. In other embodiments, at least one of R^(6D) and R^(6E) can be NH₂. In some embodiments, R^(6D) can be NHR^(6G), wherein R^(6G) can be an optionally substituted C₁₋₆ alkyl. In some embodiments, R^(6E) can be hydrogen. In other embodiments, R^(6E) can be halogen. In still other embodiments, R^(6E) can be NHR^(6H), wherein R^(6H) can be an optionally substituted C₁₋₆ alkyl. In other embodiments, R^(6D) can be NHR^(6G), wherein R^(6G) can be selected from an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2). In other embodiments, R^(6E) can be NHR^(6H), wherein R^(6H) can be selected from an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4). In some embodiments, R^(6D) and R^(6E) can be the same. In other embodiments, R^(6D) and R^(6E) can be different.

In some embodiments, B¹ can be cytosine. In some embodiments, B¹ can be an optionally substituted

wherein R^(6F) can be NHR^(6I); R^(6I) can be selected hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A5) and —C(═O)OR^(A6); and R^(A5) and R^(A6) are independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl, aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl). In some embodiments, R^(6F) can be NH₂. In other embodiments, R^(6F) can be NHR^(6I), wherein R^(6I) can be an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl or an optionally substituted C₃₋₆ cycloalkyl. In still other embodiments, R^(6F) can be NHR^(6I), wherein R^(6I) can be —C(═O)R^(A5) or —C(═O)OR^(A6). When R^(6I) is —C(═O)R^(A5) or —C(═O)OR^(A6), R^(A5) and R^(A6) can be C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl. R^(A5) and R^(A6) can also be C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl or heteroaryl, heterocyclyl. Additionally, R^(A5) and R^(A6) can be aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) or heterocyclyl(C₁₋₆ alkyl).

In some embodiments, Z¹ can be O (oxygen). In other embodiments, Z¹ can be S (sulfur).

In some embodiments, R² is not halo. In some embodiments, R² is not fluoro. In some embodiments, R^(5B) is not an —O-optionally substituted aryl. In some embodiments, R^(5B) is not an —O-unsubstituted aryl. In some embodiments, R^(5A) is not N-alanine isopropyl ester. In some embodiments, R¹ is not an optionally substituted C₁₋₆ alkyl. For example, R¹ is not an unsubstituted C₁₋₆ alkyl, such as methyl. In some embodiments, B¹ is not an optionally substituted uracil, for example, a halo-substituted uracil. In some embodiment, when both ------- are each absent; R^(P) is absent; R³ is OH or —OC(═O)R⁸; R² is F; and R¹ is methyl, ethyl or ethenyl; then R⁴ cannot be selected from H and

wherein R^(5B) is an —O-unsubstituted aryl; R^(5A) is

and Z¹ is oxygen. In some embodiments, R² is not halo (such as fluoro) when B¹ is uracil. In some embodiments, a compound of Formula (I) is not a compound in WO 2013/092481 (filed Dec. 17, 2012).

Example structures of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing. In some embodiments of this paragraph, R³ can be OH. In some embodiments of this paragraph, R^(6C) can be an unsubstituted C₁₋₆ alkyl, such as CH₂CH₃. In some embodiments of this paragraph, R^(p1) can be —O-unsubstituted C₁₋₆ alkyl. In some embodiments, of this paragraph, R⁴ can be H. In other embodiments, of this paragraph, R⁴ can be a phosphoroamidate group. In still other embodiments, of this paragraph, R⁴ can be a phosphate group (such as a mono-, di- or tri-phosphate). In yet still other embodiments, of this paragraph, R⁴ can be a thiophosphoroamidate group. In some embodiments, of this paragraph, R⁴ can be thiophosphate group (such as an alpha-thiomono-, alpha-thiodi- or alpha-thiotri-phosphate). In some embodiments of this paragraph, R^(p1) can be —O-ethyl, —O-isopropyl or —O-isobutyl.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Still further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.

As described herein, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have R⁴ being

R^(5A) being an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; and R^(5B) being an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, an —O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. By neutralizing the charge on the phosphate or thiophosphate, penetration of the cell membrane may be facilitated as a result of the increased lipophilicity of the compound. Once absorbed and taken inside the cell, the groups attached to the phosphorus can be easily removed by esterases, proteases and/or other enzymes. In some embodiments, the groups attached to the phosphorus can be removed by simple hydrolysis. Inside the cell, the phosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate. Likewise, the thio-phosphate may be metabolized to the alpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, in some embodiments, varying the substituents on a compound described herein, such as compound of Formula (I), can help maintain the efficacy of such the compound by reducing undesirable effects, such as isomerization.

In some embodiments, the phosphorylation of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can be stereoselective. For example, a thio-monophosphate of a compound of Formula (I) can be phosphorylated to give an alpha-thiodiphosphate and/or an alpha-thiotriphosphate compound that can be enriched in the (R) or (S) diastereomer with respect to the 5′-O-phosphorous atom. For example, one of the (R) and (S) configuration with respect to the 5′-O-phosphorous atom of the alpha-thiodiphosphate and/or the alpha-thiotriphosphate compound can be present in an amount >50%, ≥75%, ≥90%, ≥95% or ≥99% compared to the amount of the other of the (R) or (S) configuration with respect to the 5′-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can result in the formation of a compound that has the (R)-configuration at the 5′-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can result in formation of a compound that has the (S)-configuration at the 5′-O-phosphorous atom.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of HCV replication. For example, compounds of Formula (I) can contain a moiety at the 2′-carbon position such that once the compound is incorporated into an RNA chain of HCV no further elongation is observed to occur. For example, a compound of Formula (I) can contain a 2′-carbon modification wherein R¹ is a non-hydrogen group selected from an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be more resistant to hydrolysis and/or more resistant to enzymatic transformations. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have increased metabolic stability, increased plasma stability, can be more resistant to hydrolysis and/or can be more resistant to enzymatic transformations compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have improved properties. A non-limiting list of example properties include, but are not limited to, increased biological half-life, increased bioavailability, increase potency, a sustained in vivo response, increased dosing intervals, decreased dosing amounts, decreased cytotoxicity, reduction in required amounts for treating disease conditions, reduction in viral load, reduction in time to seroconversion (i.e., the virus becomes undetectable in patient serum), increased sustained viral response, a reduction of morbidity or mortality in clinical outcomes, increased subject compliance, decreased liver conditions (such as liver fibrosis, liver cirrhosis and/or liver cancer), and compatibility with other medications. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have a biological half-life of greater than 24 hours. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have a biological half-life greater than a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have more potent antiviral activity (for example, a lower EC₅₀ in an HCV replicon assay) as compared to the current standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, does not significantly inhibit mitochondrial function of the mitochondrial RNA polymerase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is incorporated in the human mitochondrial RNA polymerase less than 10% compared to the natural 5′-triphosphate nucleotide with the same B¹.

Additionally, in some embodiments, the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate in a compound of Formula (I) can increase the stability of the compound by inhibiting its degradation. Also, in some embodiments, the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can make the compound more resistant to cleavage in vivo and provide sustained, extended efficacy. In some embodiments, a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can facilitate the penetration of the cell membrane by a compound of Formula (I) by making the compound more lipophilic. In some embodiments, a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can have improved oral bioavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity. In some embodiments, for comparison purposes, a compound of Formula (I) can be compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position.

Synthesis

Compounds of Formula (I) and those described herein may be prepared in various ways. General synthetic routes to the compound of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown in Scheme 1 and 2, and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

Compounds of Formula (I) can be prepared using various methods known to those skilled in the art. Examples of methods are shown in Schemes 1 and 2. Suitable phosphorus containing precursors can be commercially obtained or prepared by synthetic methods known to those skilled in the art. Examples of general structures of phosphorus containing precursors are shown in Schemes 1 and 2, and include phosphorochloridates and thiophosphorochloridates. Suitable phosphorochloridates and thiophosphorochloridates are commercially available and/or can be synthetically prepared.

One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, R^(1a), R^(2a), R^(3a) and B^(1a) can be the same as R¹, R², R³ and B¹ as described herein for Formula (I). In some embodiments, a compound of Formula (I) can be generated from a compound of Formula (A) and a compound of Formula (B) or a compound of Formula (A) and a compound of Formula (C) using an organometallic reagent, such as a Grignard reagent. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides. In other embodiments, an appropriate base can be used to form a compound of Formula (I). Examples of suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole)).

When compounds of Formula (I) has Z¹ being sulfur, the sulfur can be added in various manners. In some embodiments, the sulfur can be part of the phosphorus containing precursor, for example,

Alternatively, one of the oxygens attached to the phosphorus can be exchanged with a sulfur using a sulfurization reagent. Suitable sulfurization agents are known to those skilled in the art, and include, but are not limited to, elemental sulfur, Lawesson's reagent, cyclooctasulfur, 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage's reagent), 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

A phosphorus containing precursor can be coupled to the nucleoside, for example, a compound of Formula (A). Following the coupling of the phosphorus containing precursor, any leaving groups can be cleaved under suitable conditions, such as hydrolysis. In Scheme 2, R^(1a), R^(2a), R^(3a) and B^(1a) can be the same as R¹, R², R³ and B¹ as described herein for Formula (I). Further phosphorus containing groups can be added using methods known to those skilled in the art, for example using a pyrophosphate. If desired, one or more bases can be used during the addition of each phosphorus-containing group. Examples of suitable bases are described herein.

As described herein, in some embodiments, R² and R³ can be each an oxygen atom, wherein the oxygen atoms are linked together by a carbonyl groups. The —O—C(═O)—O— group can be formed using methods known to those skilled in the art. For example, a compound of Formula (I), wherein R² and R³ are both hydroxy groups, can be treated with 1,1′-carbonyldiimidazole (CDI).

In some embodiments, R² and/or R³ can be —OC(═O)R¹² and —OC(═O)R⁸, respectively. The —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the 2′- and 3′-positions using various methods known to those skilled in the art. As an example, a compound of Formula (I), wherein R² and R³ are both hydroxy groups, can be treated with an alkyl anhydride (e.g., acetic anhydride and propionic anhydride) or an alkyl acid chloride (e.g., acetylchloride). If desired, a catalyst can be used to facilitate the reaction. An example of suitable catalyst is 4-dimethylaminopyridine (DMAP). Alternatively, the —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the 2′- and 3′-positions by reacting an alkyl acid (e.g. acetic acid and propionic acid) in the presences of a carbodiimide or a coupling reagent. Examples of carbodiimides include, but are not limited to, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

To reduce the formation of side products, one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups. As an example, if R² and/or R³ is/are hydroxy group(s), the hydroxy group(s) can be protected with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy) trityl (TBTr), 4,4′,4″-tris (4,5-dichlorophthalimido) trityl (CPTr), 4,4′,4″-tris (levulinyloxy) trityl (TLTr), p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl, p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl, 9-(4-octadecyloxyphenyl) xanthen-9-yl, 1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl, 4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups are described herein and include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. Alternatively, R² and/or R³ can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester; suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3-(benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal, 1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal and 1-(4-methoxyphenyl)ethylidene ketal.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (for example, a single diastereomer is present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition can include a concentration of one diastereomer of >50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, or ≥98%, as compared to the total concentration of the other diastereomers. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. A pharmaceutical composition is suitable for human and/or veterinary applications.

The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods of Use

Some embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof. Other embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject identified as suffering from the disease or condition an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relates to a method of ameliorating or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein (for example, a compound of Formula (I)), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein. Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to methods of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

In some embodiments, the compound can be a compound of Formula (I), or a pharmaceutical acceptable salt thereof, wherein R⁴ is hydrogen. In other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is a mono, di, or triphosphate, or a pharmaceutically acceptable salt of the foregoing. In still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate, or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of the foregoing. In yet still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is phosphoroamidate or phosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is thiophosphoroamidate or thiophosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutical acceptable salt thereof, that can be used to ameliorating and/or treating a viral infection (for example, a HCV infection) and/or inhibit replication of a virus (such as a HCV virus) can be any of the embodiments provided in any of the embodiments described above beginning at the first paragraph after the section heading entitled “Compounds” and ending with the sentence: “In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.”

HCV is an enveloped positive strand RNA virus in the Flaviviridae family. There are various nonstructural proteins of HCV, such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA.

Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include contacting a cell infected with hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include administering to a subject infected with hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a RNA dependent RNA polymerase, and thus, inhibit the replication of HCV RNA. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).

Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrhosis and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof), wherein the liver condition is caused by a HCV infection. Some embodiments described herein relate to a method of increasing liver function in a subject having a HCV infection that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof). Also contemplated is a method for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof). In some embodiments, this method can include slowing or halting the progression of liver disease. In other embodiments, the course of the disease can be reversed, and stasis or improvement in liver function is contemplated. In some embodiments, liver fibrosis, liver cirrhosis and/or liver cancer can be treated; liver function can be increased; virus-caused liver damage can be reduced or eliminated; progression of liver disease can be slowed or halted; the course of the liver disease can be reversed and/or liver function can be improved or maintained by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.)

There are a variety of genotypes of HCV, and a variety of subtypes within each genotype. For example, at present it is known that there are eleven (numbered 1 through 11) main genotypes of HCV, although others have classified the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, can be effective to treat at least one genotype of HCV. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat all 11 genotypes of HCV. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat 3 or more, 5 or more, 7 or more, or 9 or more genotypes of HCV. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable salt thereof can be more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable salt thereof, can be more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).

Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, a reduction in the rate of liver function decrease; stasis in liver function; improvement in liver function; reduction in one or more markers of liver dysfunction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase and/or other indicator of disease response. Similarly, successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can reduce the incidence of liver cancer in HCV infected subjects.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce HCV viral titers to undetectable levels, for example, to about 100 to about 500, to about 50 to about 100, to about 10 to about 50, or to about 15 to about 25 international units/mL serum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce HCV viral load compared to the HCV viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, wherein the HCV viral load is measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be an amount that is effective to reduce HCV viral load to lower than about 25 international units/mL serum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a reduction in HCV viral titer in the serum of the subject in the range of about 1.5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the HCV viral load can be measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of the hepatitis C virus relative to pre-treatment levels in a subject, as determined after completion of the treatment regime (for example, 1 month after completion). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of the replication of the hepatitis C virus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of the hepatitis C virus replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of the hepatitis C virus replication compared to the reduction of the hepatitis C virus reduction achieved by pegylated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the same reduction as that standard of care therapy in a shorter period of time, for example, in one month, two months, or three months, as compared to the reduction achieved after six months of standard of care therapy with ribavirin and pegylated interferon.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 200, less than about 100, less than about 25, or less than about 15 international units per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can reduce a level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated subject, or to a placebo-treated subject. Methods of measuring serum markers are known to those skilled in the art and include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker. A non-limiting list of examples of markers includes measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods. In general, an ALT level of less than about 45 IU/L (international units/liter), an AST in the range of 10-34 IU/L, ALP in the range of 44-147 IU/L, GGT in the range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.

Subjects who are clinically diagnosed with HCV infection include “naïve” subjects (e.g., subjects not previously treated for HCV, particularly those who have not previously received IFN-alpha-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV (“treatment failure” subjects). Treatment failure subjects include “non-responders” (i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV (≤0.5 log IU/mL), for example, a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy); and “relapsers” (i.e., subjects who were previously treated for HCV, for example, who received a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a treatment failure subject suffering from HCV. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a non-responder subject suffering from HCV. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a relapsed subject suffering from HCV.

After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with an HCV strain that is resistant to one or more different anti-HCV agents (for example, an agent used in a conventional standard of care). In some embodiments, development of resistant HCV strains is delayed when a subject is treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of HCV strains resistant to other HCV drugs (such as an agent used in a conventional standard of care).

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject for whom other anti-HCV medications are contraindicated. For example, administration of pegylated interferon alpha in combination with ribavirin is contraindicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) and other subjects at risk from the hematologic side effects of current therapy. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided to a subject that is hypersensitive to interferon and/or ribavirin.

Some subjects being treated for HCV experience a viral load rebound. The term “viral load rebound” as used herein refers to a sustained ≥0.5 log IU/mL increase of viral load above nadir before the end of treatment, where nadir is a ≥0.5 log IU/mL decrease from baseline. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.

The standard of care for treating HCV has been associated with several side effects (adverse events). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can decrease the number and/or severity of side effects that can be observed in HCV patients being treated with ribavirin and pegylated interferon according to the standard of care. Examples of side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, depression, severe depression, suicidal ideation, anemia, low white blood cell counts, and thinning of hair. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided to a subject that discontinued a HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents (for example, an agent used in a conventional standard of care).

Table 1 provides some embodiments of the percentage improvement obtained using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to the standard of care. Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art.

TABLE 1 Percentage Percentage Percentage of non- Percentage of of viral load Number of Severity of responders of relapsers resistance rebound side effects side effects 10% less 10% less 10% less 10% less 10% less 10% less 25% less 25% less 25% less 25% less 25% less 25% less 40% less 40% less 40% less 40% less 40% less 40% less 50% less 50% less 50% less 50% less 50% less 50% less 60% less 60% less 60% less 60% less 60% less 60% less 70% less 70% less 70% less 70% less 70% less 70% less 80% less 80% less 80% less 80% less 80% less 80% less 90% less 90% less 90% less 90% less 90% less 90% less about 10% about 10% about 10% about 10% to about 10% to about 10% to to about to about to about about 30% about 30% about 30% 30% less 30% less 30% less less less less about 20% about 20% about 20% about 20% to about 20% to about 20% to to about to about to about about 50% about 50% about 50% 50% less 50% less 50% less less less less about 30% about 30% about 30% about 30% to about 30% to about 30% to to about to about to about about 70% about 70% about 70% 70% less 70% less 70% less less less less about 20% about 20% about 20% about 20% to about 20% to about 20% to to about to about to about about 80% about 80% about 80% 80% less 80% less 80% less less less less

As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day to a subject suffering from a HCV infection. In some embodiments, the total time of the treatment regime with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can less compared to the total time of the treatment regime with the standard of care.

In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀ values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.

Combination Therapies

In some embodiments, the compounds disclosed herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more additional agent(s). Examples of additional agents that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include, but are not limited to, agents currently used in a conventional standard of care for treating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (AA), (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (AA), or a pharmaceutically acceptable salt thereof), compounds of Formula (BB) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable salt thereof), compounds of Formula (CC) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (CC), or a pharmaceutically acceptable salt thereof), and/or combinations thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used with one, two, three or more additional agents described herein. A non-limiting list of examples of combinations of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in Tables A, B, C, D and E.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with an agent(s) currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound disclosed herein can be used in combination with Pegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin, Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin, Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, or ribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be substituted for an agent currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in place of ribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with an interferon, such as a pegylated interferon. Examples of suitable interferons include, but are not limited to, Pegylated interferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a HCV protease inhibitor. A non-limiting list of example HCV protease inhibitors include the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof. Additional HCV protease inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include VP-19744, PSI-879, VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479, R-1626, R-7182, MK-0608, INX-8014, INX-8018, A-848837, A-837093, BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and those disclosed in PCT Publication No. WO 2012/142085, which is hereby incorporated by reference for the limited purpose of its disclosure of HCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors. A non-limiting list of example HCV protease inhibitors includes the compounds numbered 1001-1016 in FIG. 1.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189, PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of 4′-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof. A non-limiting list of example nucleoside inhibitors includes compounds numbered 2001-2012 in FIG. 2. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A non-limiting list of example non-nucleoside inhibitors includes the compounds numbered 3001-3014 in FIG. 3. Further HCV polymerase inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include VX-500, VX-813, VBY-376, TMC-435350, EZ-058, EZ-063, GS-9132, ACH-1095, IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587, VX-985, and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a NS5A inhibitor. Examples of NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4012 in FIG. 4. Additional NS5A inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include A-832, PPI-1301 and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122, cyclosporin A and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5012 in FIG. 5.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (AA), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (AA), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2013/0164261, published Jun. 27, 2013, the contents of which are incorporated by reference in its entirety):

wherein: B^(AA1) can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^(AA1) can be selected from O⁻, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^(AA2) can be absent or selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and

wherein R^(AA6), R^(AA7) and R^(AA8) can be independently absent or hydrogen, and n^(AA) can be 0 or 1; provided that when R^(AA1) is O⁻ or OH, then R^(AA2) is absent, hydrogen or

R^(AA3) can be selected from hydrogen, halogen, —OR^(AA9) and —OC(═O)R^(AA10); R^(AA4) can be selected from halogen, and —OC(═O)R^(AA12); or R^(AA3) and R^(AA4) can be both an oxygen atom which are linked together by a carbonyl group; R^(AA5) can be selected from an optionally substituted C₂₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆ cycloalkyl; or R^(AA4) and R^(AA5) together can form —(C₁₋₆ alkyl)-O— or —O—(C₁₋₆ alkyl)-; R^(AA9) and R^(AA11) can be independently hydrogen or an optionally substituted C₁₋₆ alkyl; and R^(AA10) and R^(AA12) can be independently an optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl. A non-limiting list of examples of compounds of Formula (AA) includes the compounds numbered 7000-7027 in FIG. 7.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0165286, published Jun. 28, 2012, the contents of which are incorporated by reference in their entireties):

wherein B^(BB1) can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; X^(BB) can be O (oxygen) or S (sulfur); R^(BB1) can be selected from —Z^(BB)—R^(BB9), an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; Z^(BB) can be selected from O (oxygen), S (sulfur) and N(R^(BB10)); R^(BB2) and R^(BB3) can be independently selected from hydrogen, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl, an optionally substituted C₁₋₆ haloalkyl and an optionally substituted aryl(C₁₋₆ alkyl); or R^(BB2) and R^(BB3) can be taken together to form a group selected from an optionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆ cycloalkenyl, an optionally substituted C₃₋₆ aryl and an optionally substituted C₃₋₆ heteroaryl; R^(BB4) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl and an optionally substituted allenyl; R^(BB5) can be hydrogen or an optionally substituted C₁₋₆ alkyl; R^(BB6) can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(BB11) and —OC(═O)R^(BB12); R^(BB7) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(BB13) and —OC(═O)R^(BB14); R^(BB8) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(BB15) and —OC(═O)R^(BB16); R^(BB9) can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C₁₋₆alkyl), an optionally substituted heteroaryl(C₁₋₆alkyl) and an optionally substituted heterocyclyl(C₁₋₆alkyl); R^(BB10) can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C₁₋₆alkyl), an optionally substituted heteroaryl(C₁₋₆alkyl) and an optionally substituted heterocyclyl(C₁₋₆alkyl); R^(BB11), R^(BB13) and R^(BB15) can be independently hydrogen or an optionally substituted C₁₋₆ alkyl; and R^(BB12), R^(BB14) and R^(BB16) can be independently an optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl. In some embodiments, at least one of R^(BB2) and R^(BB3) is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8016 in FIG. 8.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (CC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (CC), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0071434, published Mar. 22, 2012, the contents of which are incorporated by reference in its entirety):

wherein B^(CC1) can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^(CC1) can be selected from O⁻, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^(CC2) can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and

wherein R^(CC19), R^(CC20) and R^(CC21) can be independently absent or hydrogen, and n^(CC) can be 0 or 1; provided that when R^(CC1) is O⁻ or OH, then R^(CC2) is

R^(CC3a) and R^(CC3b) can be independently selected from hydrogen, deuterium, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl, an optionally substituted C₁₋₆ haloalkyl and aryl(C₁₋₆ alkyl); or R^(CC3a) and R^(CC3b) can be taken together to form an optionally substituted C₃₋₆ cycloalkyl; R^(CC4) can be selected from hydrogen, azido, an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(CC5) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC10) and —OC(═O)R^(CC11); R^(CC6) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC12) and —OC(═O)R^(CC13); R^(CC7) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC14) and —OC(═O)R^(CC15); or R^(CC6) and R^(CC7) can be both oxygen atoms and linked together by a carbonyl group; R^(CC8) can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC16) and —OC(═O)R^(CC17); R^(CC9) can be selected from hydrogen, azido, cyano, an optionally substituted C₁₋₆ alkyl and —OR^(CC18); R^(CC10), R^(CC12), R^(CC14), R^(CC16) and R^(CC18) can be independently selected from hydrogen and an optionally substituted C₁₋₆ alkyl; and R^(CC11), R^(CC13), R^(CC15) and R^(CC17) can be independently selected from an optionally substituted C₁₋₆ alkyl and an optionally substituted C₃₋₆ cycloalkyl. In some embodiments, when R^(CC3a), R^(CC3b), R^(CC4), R^(CC5), R^(CC7), R^(CC8) and R^(CC9) are all hydrogen, then R^(CC6) is not azido. In some embodiments, R^(CC2) cannot be

when R^(CC3a) is hydrogen, R^(CC3b) is hydrogen, R^(CC4) is H, R^(CC5) is OH or H, R^(CC6) is hydrogen, OH, or —OC(═O)CH₃, R^(CC7) is hydrogen, OH, OCH₃ or —OC(═O)CH₃, R^(CC8) is hydrogen, OH or OCH₃, R^(CC9) is H and B^(CC1) is an optionally substituted adenine, an optionally substituted guanine, an optionally substituted uracil or an optionally substituted hypoxanthine. In some embodiments, R^(CC2) cannot be

A non-limiting list of examples of compounds of Formula (CC) includes the compounds numbered 6000-6078 in FIG. 6.

Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include administering to a subject suffering from the HCV infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include administering to a subject infected with the hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt the thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

The dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are within the knowledge of those skilled in the art. For example, when performing a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.

The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of all additional agents.

In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in an additive effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a strongly synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.

As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound). As used herein, the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.

A potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 1-8 (including pharmaceutically acceptable salts thereof) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic result when one or more compounds of FIGS. 1-8 (including pharmaceutically acceptable salts thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound in FIGS. 1-8 (including a pharmaceutically acceptable salt thereof), can be less compared to the amount of the compound in FIGS. 1-8 (including a pharmaceutically acceptable salt thereof), needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) thereof; different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); little to no significant effects on cytochrome P450; little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); greater percentage of subjects achieving a sustained viral response compared to when a compound is administered as monotherapy and/or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.

A non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C, D and E. Each numbered X and Y compound in Tables A, B, C, D and E has a corresponding name and/or structure provided in FIGS. 1-8. The numbered compounds in Tables A, B, C, D and E includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable salt thereof. For example, 1001 includes the compound corresponding to 1001, pharmaceutically acceptable salts thereof, and pharmaceutical compositions that include compound 1001 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C, D and E are designated by the formula X:Y, which represents a combination of a compound X with a compound Y. For example, the combination designated as 1001:9004 in Table A represents a combination of compound 1001 with compound 9004, including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Thus, the combination designated as 1001:9004 in Table A represents the combination of Telaprevir (compound 1001, as shown in FIG. 1) and

(compound 9004, as shown in FIG. 9), including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Each of the combinations provided in Tables A, B, C, D and E can be used with one, two, three or more additional agents described herein. In some embodiments described herein, the combination of agents can be used to treat, ameliorate and/or inhibit a virus and/or a viral infection, wherein the virus can be HCV and the viral infection can be an HCV viral infection.

TABLE A Example combinations of a compound X with a compound Y. X:Y X:Y X:Y X:Y X:Y X:Y 1001:9000 1001:9001 1001:9002 1001:9003 1001:9004 1001:9005 1002:9000 1002:9001 1002:9002 1002:9003 1002:9004 1002:9005 1003:9000 1003:9001 1003:9002 1003:9003 1003:9004 1003:9005 1004:9000 1004:9001 1004:9002 1004:9003 1004:9004 1004:9005 1005:9000 1005:9001 1005:9002 1005:9003 1005:9004 1005:9005 1006:9000 1006:9001 1006:9002 1006:9003 1006:9004 1006:9005 1007:9000 1007:9001 1007:9002 1007:9003 1007:9004 1007:9005 1008:9000 1008:9001 1008:9002 1008:9003 1008:9004 1008:9005 1009:9000 1009:9001 1009:9002 1009:9003 1009:9004 1009:9005 1010:9000 1010:9001 1010:9002 1010:9003 1010:9004 1010:9005 1011:9000 1011:9001 1011:9002 1011:9003 1011:9004 1011:9005 1012:9000 1012:9001 1012:9002 1012:9003 1012:9004 1012:9005 1013:9000 1013:9001 1013:9002 1013:9003 1013:9004 1013:9005 1014:9000 1014:9001 1014:9002 1014:9003 1014:9004 1014:9005 1015:9000 1015:9001 1015:9002 1015:9003 1015:9004 1015:9005 1016:9000 1016:9001 1016:9002 1016:9003 1016:9004 1016:9005 2001:9000 2001:9001 2001:9002 2001:9003 2001:9004 2001:9005 2002:9000 2002:9001 2002:9002 2002:9003 2002:9004 2002:9005 2003:9000 2003:9001 2003:9002 2003:9003 2003:9004 2003:9005 2004:9000 2004:9001 2004:9002 2004:9003 2004:9004 2004:9005 2005:9000 2005:9001 2005:9002 2005:9003 2005:9004 2005:9005 2006:9000 2006:9001 2006:9002 2006:9003 2006:9004 2006:9005 2007:9000 2007:9001 2007:9002 2007:9003 2007:9004 2007:9005 2008:9000 2008:9001 2008:9002 2008:9003 2008:9004 2008:9005 2009:9000 2009:9001 2009:9002 2009:9003 2009:9004 2009:9005 2010:9000 2010:9001 2010:9002 2010:9003 2010:9004 2010:9005 2011:9000 2011:9001 2011:9002 2011:9003 2011:9004 2011:9005 2012:9000 2012:9001 2012:9002 2012:9003 2012:9004 2012:9005 1001:9006 1001:9007 1001:9008 1001:9009 1001:9010 1001:9011 1002:9006 1002:9007 1002:9008 1002:9009 1002:9010 1002:9011 1003:9006 1003:9007 1003:9008 1003:9009 1003:9010 1003:9011 1004:9006 1004:9007 1004:9008 1004:9009 1004:9010 1004:9011 1005:9006 1005:9007 1005:9008 1005:9009 1005:9010 1005:9011 1006:9006 1006:9007 1006:9008 1006:9009 1006:9010 1006:9011 1007:9006 1007:9007 1007:9008 1007:9009 1007:9010 1007:9011 1008:9006 1008:9007 1008:9008 1008:9009 1008:9010 1008:9011 1009:9006 1009:9007 1009:9008 1009:9009 1009:9010 1009:9011 1010:9006 1010:9007 1010:9008 1010:9009 1010:9010 1010:9011 1011:9006 1011:9007 1011:9008 1011:9009 1011:9010 1011:9011 1012:9006 1012:9007 1012:9008 1012:9009 1012:9010 1012:9011 1013:9006 1013:9007 1013:9008 1013:9009 1013:9010 1013:9011 1014:9006 1014:9007 1014:9008 1014:9009 1014:9010 1014:9011 1015:9006 1015:9007 1015:9008 1015:9009 1015:9010 1015:9011 1016:9006 1016:9007 1016:9008 1016:9009 1016:9010 1016:9011 2001:9006 2001:9007 2001:9008 2001:9009 2001:9010 2001:9011 2002:9006 2002:9007 2002:9008 2002:9009 2002:9010 2002:9011 2003:9006 2003:9007 2003:9008 2003:9009 2003:9010 2003:9011 2004:9006 2004:9007 2004:9008 2004:9009 2004:9010 2004:9011 2005:9006 2005:9007 2005:9008 2005:9009 2005:9010 2005:9011 2006:9006 2006:9007 2006:9008 2006:9009 2006:9010 2006:9011 2007:9006 2007:9007 2007:9008 2007:9009 2007:9010 2007:9011 2008:9006 2008:9007 2008:9008 2008:9009 2008:9010 2008:9011 2009:9006 2009:9007 2009:9008 2009:9009 2009:9010 2009:9011 2010:9006 2010:9007 2010:9008 2010:9009 2010:9010 2010:9011 2011:9006 2011:9007 2011:9008 2011:9009 2011:9010 2011:9011 2012:9006 2012:9007 2012:9008 2012:9009 2012:9010 2012:9011 1001:9012 1001:9013 1001:9014 1001:9015 1001:9016 1001:9017 1002:9012 1002:9013 1002:9014 1002:9015 1002:9016 1002:9017 1003:9012 1003:9013 1003:9014 1003:9015 1003:9016 1003:9017 1004:9012 1004:9013 1004:9014 1004:9015 1004:9016 1004:9017 1005:9012 1005:9013 1005:9014 1005:9015 1005:9016 1005:9017 1006:9012 1006:9013 1006:9014 1006:9015 1006:9016 1006:9017 1007:9012 1007:9013 1007:9014 1007:9015 1007:9016 1007:9017 1008:9012 1008:9013 1008:9014 1008:9015 1008:9016 1008:9017 1009:9012 1009:9013 1009:9014 1009:9015 1009:9016 1009:9017 1010:9012 1010:9013 1010:9014 1010:9015 1010:9016 1010:9017 1011:9012 1011:9013 1011:9014 1011:9015 1011:9016 1011:9017 1012:9012 1012:9013 1012:9014 1012:9015 1012:9016 1012:9017 1013:9012 1013:9013 1013:9014 1013:9015 1013:9016 1013:9017 1014:9012 1014:9013 1014:9014 1014:9015 1014:9016 1014:9017 1015:9012 1015:9013 1015:9014 1015:9015 1015:9016 1015:9017 1016:9012 1016:9013 1016:9014 1016:9015 1016:9016 1016:9017 2001:9012 2001:9013 2001:9014 2001:9015 2001:9016 2001:9017 2002:9012 2002:9013 2002:9014 2002:9015 2002:9016 2002:9017 2003:9012 2003:9013 2003:9014 2003:9015 2003:9016 2003:9017 2004:9012 2004:9013 2004:9014 2004:9015 2004:9016 2004:9017 2005:9012 2005:9013 2005:9014 2005:9015 2005:9016 2005:9017 2006:9012 2006:9013 2006:9014 2006:9015 2006:9016 2006:9017 2007:9012 2007:9013 2007:9014 2007:9015 2007:9016 2007:9017 2008:9012 2008:9013 2008:9014 2008:9015 2008:9016 2008:9017 2009:9012 2009:9013 2009:9014 2009:9015 2009:9016 2009:9017 2010:9012 2010:9013 2010:9014 2010:9015 2010:9016 2010:9017 2011:9012 2011:9013 2011:9014 2011:9015 2011:9016 2011:9017 2012:9012 2012:9013 2012:9014 2012:9015 2012:9016 2012:9017 1001:9018 1001:9019 1001:9020 1001:9021 1001:9022 1001:9023 1002:9018 1002:9019 1002:9020 1002:9021 1002:9022 1002:9023 1003:9018 1003:9019 1003:9020 1003:9021 1003:9022 1003:9023 1004:9018 1004:9019 1004:9020 1004:9021 1004:9022 1004:9023 1005:9018 1005:9019 1005:9020 1005:9021 1005:9022 1005:9023 1006:9018 1006:9019 1006:9020 1006:9021 1006:9022 1006:9023 1007:9018 1007:9019 1007:9020 1007:9021 1007:9022 1007:9023 1008:9018 1008:9019 1008:9020 1008:9021 1008:9022 1008:9023 1009:9018 1009:9019 1009:9020 1009:9021 1009:9022 1009:9023 1010:9018 1010:9019 1010:9020 1010:9021 1010:9022 1010:9023 1011:9018 1011:9019 1011:9020 1011:9021 1011:9022 1011:9023 1012:9018 1012:9019 1012:9020 1012:9021 1012:9022 1012:9023 1013:9018 1013:9019 1013:9020 1013:9021 1013:9022 1013:9023 1014:9018 1014:9019 1014:9020 1014:9021 1014:9022 1014:9023 1015:9018 1015:9019 1015:9020 1015:9021 1015:9022 1015:9023 1016:9018 1016:9019 1016:9020 1016:9021 1016:9022 1016:9023 2001:9018 2001:9019 2001:9020 2001:9021 2001:9022 2001:9023 2002:9018 2002:9019 2002:9020 2002:9021 2002:9022 2002:9023 2003:9018 2003:9019 2003:9020 2003:9021 2003:9022 2003:9023 2004:9018 2004:9019 2004:9020 2004:9021 2004:9022 2004:9023 2005:9018 2005:9019 2005:9020 2005:9021 2005:9022 2005:9023 2006:9018 2006:9019 2006:9020 2006:9021 2006:9022 2006:9023 2007:9018 2007:9019 2007:9020 2007:9021 2007:9022 2007:9023 2008:9018 2008:9019 2008:9020 2008:9021 2008:9022 2008:9023 2009:9018 2009:9019 2009:9020 2009:9021 2009:9022 2009:9023 2010:9018 2010:9019 2010:9020 2010:9021 2010:9022 2010:9023 2011:9018 2011:9019 2011:9020 2011:9021 2011:9022 2011:9023 2012:9018 2012:9019 2012:9020 2012:9021 2012:9022 2012:9023 1001:9024 1001:9025 1001:9026 1001:9027 1001:9028 1001:9029 1002:9024 1002:9025 1002:9026 1002:9027 1002:9028 1002:9029 1003:9024 1003:9025 1003:9026 1003:9027 1003:9028 1003:9029 1004:9024 1004:9025 1004:9026 1004:9027 1004:9028 1004:9029 1005:9024 1005:9025 1005:9026 1005:9027 1005:9028 1005:9029 1006:9024 1006:9025 1006:9026 1006:9027 1006:9028 1006:9029 1007:9024 1007:9025 1007:9026 1007:9027 1007:9028 1007:9029 1008:9024 1008:9025 1008:9026 1008:9027 1008:9028 1008:9029 1009:9024 1009:9025 1009:9026 1009:9027 1009:9028 1009:9029 1010:9024 1010:9025 1010:9026 1010:9027 1010:9028 1010:9029 1011:9024 1011:9025 1011:9026 1011:9027 1011:9028 1011:9029 1012:9024 1012:9025 1012:9026 1012:9027 1012:9028 1012:9029 1013:9024 1013:9025 1013:9026 1013:9027 1013:9028 1013:9029 1014:9024 1014:9025 1014:9026 1014:9027 1014:9028 1014:9029 1015:9024 1015:9025 1015:9026 1015:9027 1015:9028 1015:9029 1016:9024 1016:9025 1016:9026 1016:9027 1016:9028 1016:9029 2001:9024 2001:9025 2001:9026 2001:9027 2001:9028 2001:9029 2002:9024 2002:9025 2002:9026 2002:9027 2002:9028 2002:9029 2003:9024 2003:9025 2003:9026 2003:9027 2003:9028 2003:9029 2004:9024 2004:9025 2004:9026 2004:9027 2004:9028 2004:9029 2005:9024 2005:9025 2005:9026 2005:9027 2005:9028 2005:9029 2006:9024 2006:9025 2006:9026 2006:9027 2006:9028 2006:9029 2007:9024 2007:9025 2007:9026 2007:9027 2007:9028 2007:9029 2008:9024 2008:9025 2008:9026 2008:9027 2008:9028 2008:9029 2009:9024 2009:9025 2009:9026 2009:9027 2009:9028 2009:9029 2010:9024 2010:9025 2010:9026 2010:9027 2010:9028 2010:9029 2011:9024 2011:9025 2011:9026 2011:9027 2011:9028 2011:9029 2012:9024 2012:9025 2012:9026 2012:9027 2012:9028 2012:9029 1001:9030 1001:9031 1001:9032 1001:9033 1001:9034 1001:9035 1002:9030 1002:9031 1002:9032 1002:9033 1002:9034 1002:9035 1003:9030 1003:9031 1003:9032 1003:9033 1003:9034 1003:9035 1004:9030 1004:9031 1004:9032 1004:9033 1004:9034 1004:9035 1005:9030 1005:9031 1005:9032 1005:9033 1005:9034 1005:9035 1006:9030 1006:9031 1006:9032 1006:9033 1006:9034 1006:9035 1007:9030 1007:9031 1007:9032 1007:9033 1007:9034 1007:9035 1008:9030 1008:9031 1008:9032 1008:9033 1008:9034 1008:9035 1009:9030 1009:9031 1009:9032 1009:9033 1009:9034 1009:9035 1010:9030 1010:9031 1010:9032 1010:9033 1010:9034 1010:9035 1011:9030 1011:9031 1011:9032 1011:9033 1011:9034 1011:9035 1012:9030 1012:9031 1012:9032 1012:9033 1012:9034 1012:9035 1013:9030 1013:9031 1013:9032 1013:9033 1013:9034 1013:9035 1014:9030 1014:9031 1014:9032 1014:9033 1014:9034 1014:9035 1015:9030 1015:9031 1015:9032 1015:9033 1015:9034 1015:9035 1016:9030 1016:9031 1016:9032 1016:9033 1016:9034 1016:9035 2001:9030 2001:9031 2001:9032 2001:9033 2001:9034 2001:9035 2002:9030 2002:9031 2002:9032 2002:9033 2002:9034 2002:9035 2003:9030 2003:9031 2003:9032 2003:9033 2003:9034 2003:9035 2004:9030 2004:9031 2004:9032 2004:9033 2004:9034 2004:9035 2005:9030 2005:9031 2005:9032 2005:9033 2005:9034 2005:9035 2006:9030 2006:9031 2006:9032 2006:9033 2006:9034 2006:9035 2007:9030 2007:9031 2007:9032 2007:9033 2007:9034 2007:9035 2008:9030 2008:9031 2008:9032 2008:9033 2008:9034 2008:9035 2009:9030 2009:9031 2009:9032 2009:9033 2009:9034 2009:9035 2010:9030 2010:9031 2010:9032 2010:9033 2010:9034 2010:9035 2011:9030 2011:9031 2011:9032 2011:9033 2011:9034 2011:9035 2012:9030 2012:9031 2012:9032 2012:9033 2012:9034 2012:9035 1001:9036 1001:9037 1001:9038 1001:9039 1001:9040 1001:9041 1002:9036 1002:9037 1002:9038 1002:9039 1002:9040 1002:9041 1003:9036 1003:9037 1003:9038 1003:9039 1003:9040 1003:9041 1004:9036 1004:9037 1004:9038 1004:9039 1004:9040 1004:9041 1005:9036 1005:9037 1005:9038 1005:9039 1005:9040 1005:9041 1006:9036 1006:9037 1006:9038 1006:9039 1006:9040 1006:9041 1007:9036 1007:9037 1007:9038 1007:9039 1007:9040 1007:9041 1008:9036 1008:9037 1008:9038 1008:9039 1008:9040 1008:9041 1009:9036 1009:9037 1009:9038 1009:9039 1009:9040 1009:9041 1010:9036 1010:9037 1010:9038 1010:9039 1010:9040 1010:9041 1011:9036 1011:9037 1011:9038 1011:9039 1011:9040 1011:9041 1012:9036 1012:9037 1012:9038 1012:9039 1012:9040 1012:9041 1013:9036 1013:9037 1013:9038 1013:9039 1013:9040 1013:9041 1014:9036 1014:9037 1014:9038 1014:9039 1014:9040 1014:9041 1015:9036 1015:9037 1015:9038 1015:9039 1015:9040 1015:9041 1016:9036 1016:9037 1016:9038 1016:9039 1016:9040 1016:9041 2001:9036 2001:9037 2001:9038 2001:9039 2001:9040 2001:9041 2002:9036 2002:9037 2002:9038 2002:9039 2002:9040 2002:9041 2003:9036 2003:9037 2003:9038 2003:9039 2003:9040 2003:9041 2004:9036 2004:9037 2004:9038 2004:9039 2004:9040 2004:9041 2005:9036 2005:9037 2005:9038 2005:9039 2005:9040 2005:9041 2006:9036 2006:9037 2006:9038 2006:9039 2006:9040 2006:9041 2007:9036 2007:9037 2007:9038 2007:9039 2007:9040 2007:9041 2008:9036 2008:9037 2008:9038 2008:9039 2008:9040 2008:9041 2009:9036 2009:9037 2009:9038 2009:9039 2009:9040 2009:9041 2010:9036 2010:9037 2010:9038 2010:9039 2010:9040 2010:9041 2011:9036 2011:9037 2011:9038 2011:9039 2011:9040 2011:9041 2012:9036 2012:9037 2012:9038 2012:9039 2012:9040 2012:9041 1001:9042 1001:9043 1001:9044 1001:9045 1001:9046 1001:9047 1002:9042 1002:9043 1002:9044 1002:9045 1002:9046 1002:9047 1003:9042 1003:9043 1003:9044 1003:9045 1003:9046 1003:9047 1004:9042 1004:9043 1004:9044 1004:9045 1004:9046 1004:9047 1005:9042 1005:9043 1005:9044 1005:9045 1005:9046 1005:9047 1006:9042 1006:9043 1006:9044 1006:9045 1006:9046 1006:9047 1007:9042 1007:9043 1007:9044 1007:9045 1007:9046 1007:9047 1008:9042 1008:9043 1008:9044 1008:9045 1008:9046 1008:9047 1009:9042 1009:9043 1009:9044 1009:9045 1009:9046 1009:9047 1010:9042 1010:9043 1010:9044 1010:9045 1010:9046 1010:9047 1011:9042 1011:9043 1011:9044 1011:9045 1011:9046 1011:9047 1012:9042 1012:9043 1012:9044 1012:9045 1012:9046 1012:9047 1013:9042 1013:9043 1013:9044 1013:9045 1013:9046 1013:9047 1014:9042 1014:9043 1014:9044 1014:9045 1014:9046 1014:9047 1015:9042 1015:9043 1015:9044 1015:9045 1015:9046 1015:9047 1016:9042 1016:9043 1016:9044 1016:9045 1016:9046 1016:9047 2001:9042 2001:9043 2001:9044 2001:9045 2001:9046 2001:9047 2002:9042 2002:9043 2002:9044 2002:9045 2002:9046 2002:9047 2003:9042 2003:9043 2003:9044 2003:9045 2003:9046 2003:9047 2004:9042 2004:9043 2004:9044 2004:9045 2004:9046 2004:9047 2005:9042 2005:9043 2005:9044 2005:9045 2005:9046 2005:9047 2006:9042 2006:9043 2006:9044 2006:9045 2006:9046 2006:9047 2007:9042 2007:9043 2007:9044 2007:9045 2007:9046 2007:9047 2008:9042 2008:9043 2008:9044 2008:9045 2008:9046 2008:9047 2009:9042 2009:9043 2009:9044 2009:9045 2009:9046 2009:9047 2010:9042 2010:9043 2010:9044 2010:9045 2010:9046 2010:9047 2011:9042 2011:9043 2011:9044 2011:9045 2011:9046 2011:9047 2012:9042 2012:9043 2012:9044 2012:9045 2012:9046 2012:9047 1001:9048 1001:9049 1001:9050 1001:9051 1001:9052 1001:9053 1002:9048 1002:9049 1002:9050 1002:9051 1002:9052 1002:9053 1003:9048 1003:9049 1003:9050 1003:9051 1003:9052 1003:9053 1004:9048 1004:9049 1004:9050 1004:9051 1004:9052 1004:9053 1005:9048 1005:9049 1005:9050 1005:9051 1005:9052 1005:9053 1006:9048 1006:9049 1006:9050 1006:9051 1006:9052 1006:9053 1007:9048 1007:9049 1007:9050 1007:9051 1007:9052 1007:9053 1008:9048 1008:9049 1008:9050 1008:9051 1008:9052 1008:9053 1009:9048 1009:9049 1009:9050 1009:9051 1009:9052 1009:9053 1010:9048 1010:9049 1010:9050 1010:9051 1010:9052 1010:9053 1011:9048 1011:9049 1011:9050 1011:9051 1011:9052 1011:9053 1012:9048 1012:9049 1012:9050 1012:9051 1012:9052 1012:9053 1013:9048 1013:9049 1013:9050 1013:9051 1013:9052 1013:9053 1014:9048 1014:9049 1014:9050 1014:9051 1014:9052 1014:9053 1015:9048 1015:9049 1015:9050 1015:9051 1015:9052 1015:9053 1016:9048 1016:9049 1016:9050 1016:9051 1016:9052 1016:9053 2001:9048 2001:9049 2001:9050 2001:9051 2001:9052 2001:9053 2002:9048 2002:9049 2002:9050 2002:9051 2002:9052 2002:9053 2003:9048 2003:9049 2003:9050 2003:9051 2003:9052 2003:9053 2004:9048 2004:9049 2004:9050 2004:9051 2004:9052 2004:9053 2005:9048 2005:9049 2005:9050 2005:9051 2005:9052 2005:9053 2006:9048 2006:9049 2006:9050 2006:9051 2006:9052 2006:9053 2007:9048 2007:9049 2007:9050 2007:9051 2007:9052 2007:9053 2008:9048 2008:9049 2008:9050 2008:9051 2008:9052 2008:9053 2009:9048 2009:9049 2009:9050 2009:9051 2009:9052 2009:9053 2010:9048 2010:9049 2010:9050 2010:9051 2010:9052 2010:9053 2011:9048 2011:9049 2011:9050 2011:9051 2011:9052 2011:9053 2012:9048 2012:9049 2012:9050 2012:9051 2012:9052 2012:9053 1001:9054 1001:9055 1001:9056 1001:9057 1001:9058 1001:9059 1002:9054 1002:9055 1002:9056 1002:9057 1002:9058 1002:9059 1003:9054 1003:9055 1003:9056 1003:9057 1003:9058 1003:9059 1004:9054 1004:9055 1004:9056 1004:9057 1004:9058 1004:9059 1005:9054 1005:9055 1005:9056 1005:9057 1005:9058 1005:9059 1006:9054 1006:9055 1006:9056 1006:9057 1006:9058 1006:9059 1007:9054 1007:9055 1007:9056 1007:9057 1007:9058 1007:9059 1008:9054 1008:9055 1008:9056 1008:9057 1008:9058 1008:9059 1009:9054 1009:9055 1009:9056 1009:9057 1009:9058 1009:9059 1010:9054 1010:9055 1010:9056 1010:9057 1010:9058 1010:9059 1011:9054 1011:9055 1011:9056 1011:9057 1011:9058 1011:9059 1012:9054 1012:9055 1012:9056 1012:9057 1012:9058 1012:9059 1013:9054 1013:9055 1013:9056 1013:9057 1013:9058 1013:9059 1014:9054 1014:9055 1014:9056 1014:9057 1014:9058 1014:9059 1015:9054 1015:9055 1015:9056 1015:9057 1015:9058 1015:9059 1016:9054 1016:9055 1016:9056 1016:9057 1016:9058 1016:9059 2001:9054 2001:9055 2001:9056 2001:9057 2001:9058 2001:9059 2002:9054 2002:9055 2002:9056 2002:9057 2002:9058 2002:9059 2003:9054 2003:9055 2003:9056 2003:9057 2003:9058 2003:9059 2004:9054 2004:9055 2004:9056 2004:9057 2004:9058 2004:9059 2005:9054 2005:9055 2005:9056 2005:9057 2005:9058 2005:9059 2006:9054 2006:9055 2006:9056 2006:9057 2006:9058 2006:9059 2007:9054 2007:9055 2007:9056 2007:9057 2007:9058 2007:9059 2008:9054 2008:9055 2008:9056 2008:9057 2008:9058 2008:9059 2009:9054 2009:9055 2009:9056 2009:9057 2009:9058 2009:9059 2010:9054 2010:9055 2010:9056 2010:9057 2010:9058 2010:9059 2011:9054 2011:9055 2011:9056 2011:9057 2011:9058 2011:9059 2012:9054 2012:9055 2012:9056 2012:9057 2012:9058 2012:9059 1001:9060 1001:9061 1001:9062 1001:9063 1001:9064 1001:9065 1002:9060 1002:9061 1002:9062 1002:9063 1002:9064 1002:9065 1003:9060 1003:9061 1003:9062 1003:9063 1003:9064 1003:9065 1004:9060 1004:9061 1004:9062 1004:9063 1004:9064 1004:9065 1005:9060 1005:9061 1005:9062 1005:9063 1005:9064 1005:9065 1006:9060 1006:9061 1006:9062 1006:9063 1006:9064 1006:9065 1007:9060 1007:9061 1007:9062 1007:9063 1007:9064 1007:9065 1008:9060 1008:9061 1008:9062 1008:9063 1008:9064 1008:9065 1009:9060 1009:9061 1009:9062 1009:9063 1009:9064 1009:9065 1010:9060 1010:9061 1010:9062 1010:9063 1010:9064 1010:9065 1011:9060 1011:9061 1011:9062 1011:9063 1011:9064 1011:9065 1012:9060 1012:9061 1012:9062 1012:9063 1012:9064 1012:9065 1013:9060 1013:9061 1013:9062 1013:9063 1013:9064 1013:9065 1014:9060 1014:9061 1014:9062 1014:9063 1014:9064 1014:9065 1015:9060 1015:9061 1015:9062 1015:9063 1015:9064 1015:9065 1016:9060 1016:9061 1016:9062 1016:9063 1016:9064 1016:9065 2001:9060 2001:9061 2001:9062 2001:9063 2001:9064 2001:9065 2002:9060 2002:9061 2002:9062 2002:9063 2002:9064 2002:9065 2003:9060 2003:9061 2003:9062 2003:9063 2003:9064 2003:9065 2004:9060 2004:9061 2004:9062 2004:9063 2004:9064 2004:9065 2005:9060 2005:9061 2005:9062 2005:9063 2005:9064 2005:9065 2006:9060 2006:9061 2006:9062 2006:9063 2006:9064 2006:9065 2007:9060 2007:9061 2007:9062 2007:9063 2007:9064 2007:9065 2008:9060 2008:9061 2008:9062 2008:9063 2008:9064 2008:9065 2009:9060 2009:9061 2009:9062 2009:9063 2009:9064 2009:9065 2010:9060 2010:9061 2010:9062 2010:9063 2010:9064 2010:9065 2011:9060 2011:9061 2011:9062 2011:9063 2011:9064 2011:9065 2012:9060 2012:9061 2012:9062 2012:9063 2012:9064 2012:9065 1001:9066 1001:9067 1001:9068 1001:9069 1001:9070 1001:9071 1002:9066 1002:9067 1002:9068 1002:9069 1002:9070 1002:9071 1003:9066 1003:9067 1003:9068 1003:9069 1003:9070 1003:9071 1004:9066 1004:9067 1004:9068 1004:9069 1004:9070 1004:9071 1005:9066 1005:9067 1005:9068 1005:9069 1005:9070 1005:9071 1006:9066 1006:9067 1006:9068 1006:9069 1006:9070 1006:9071 1007:9066 1007:9067 1007:9068 1007:9069 1007:9070 1007:9071 1008:9066 1008:9067 1008:9068 1008:9069 1008:9070 1008:9071 1009:9066 1009:9067 1009:9068 1009:9069 1009:9070 1009:9071 1010:9066 1010:9067 1010:9068 1010:9069 1010:9070 1010:9071 1011:9066 1011:9067 1011:9068 1011:9069 1011:9070 1011:9071 1012:9066 1012:9067 1012:9068 1012:9069 1012:9070 1012:9071 1013:9066 1013:9067 1013:9068 1013:9069 1013:9070 1013:9071 1014:9066 1014:9067 1014:9068 1014:9069 1014:9070 1014:9071 1015:9066 1015:9067 1015:9068 1015:9069 1015:9070 1015:9071 1016:9066 1016:9067 1016:9068 1016:9069 1016:9070 1016:9071 2001:9066 2001:9067 2001:9068 2001:9069 2001:9070 2001:9071 2002:9066 2002:9067 2002:9068 2002:9069 2002:9070 2002:9071 2003:9066 2003:9067 2003:9068 2003:9069 2003:9070 2003:9071 2004:9066 2004:9067 2004:9068 2004:9069 2004:9070 2004:9071 2005:9066 2005:9067 2005:9068 2005:9069 2005:9070 2005:9071 2006:9066 2006:9067 2006:9068 2006:9069 2006:9070 2006:9071 2007:9066 2007:9067 2007:9068 2007:9069 2007:9070 2007:9071 2008:9066 2008:9067 2008:9068 2008:9069 2008:9070 2008:9071 2009:9066 2009:9067 2009:9068 2009:9069 2009:9070 2009:9071 2010:9066 2010:9067 2010:9068 2010:9069 2010:9070 2010:9071 2011:9066 2011:9067 2011:9068 2011:9069 2011:9070 2011:9071 2012:9066 2012:9067 2012:9068 2012:9069 2012:9070 2012:9071 1001:9072 1001:9073 1001:9074 1001:9075 1001:9076 1001:9077 1002:9072 1002:9073 1002:9074 1002:9075 1002:9076 1002:9077 1003:9072 1003:9073 1003:9074 1003:9075 1003:9076 1003:9077 1004:9072 1004:9073 1004:9074 1004:9075 1004:9076 1004:9077 1005:9072 1005:9073 1005:9074 1005:9075 1005:9076 1005:9077 1006:9072 1006:9073 1006:9074 1006:9075 1006:9076 1006:9077 1007:9072 1007:9073 1007:9074 1007:9075 1007:9076 1007:9077 1008:9072 1008:9073 1008:9074 1008:9075 1008:9076 1008:9077 1009:9072 1009:9073 1009:9074 1009:9075 1009:9076 1009:9077 1010:9072 1010:9073 1010:9074 1010:9075 1010:9076 1010:9077 1011:9072 1011:9073 1011:9074 1011:9075 1011:9076 1011:9077 1012:9072 1012:9073 1012:9074 1012:9075 1012:9076 1012:9077 1013:9072 1013:9073 1013:9074 1013:9075 1013:9076 1013:9077 1014:9072 1014:9073 1014:9074 1014:9075 1014:9076 1014:9077 1015:9072 1015:9073 1015:9074 1015:9075 1015:9076 1015:9077 1016:9072 1016:9073 1016:9074 1016:9075 1016:9076 1016:9077 2001:9072 2001:9073 2001:9074 2001:9075 2001:9076 2001:9077 2002:9072 2002:9073 2002:9074 2002:9075 2002:9076 2002:9077 2003:9072 2003:9073 2003:9074 2003:9075 2003:9076 2003:9077 2004:9072 2004:9073 2004:9074 2004:9075 2004:9076 2004:9077 2005:9072 2005:9073 2005:9074 2005:9075 2005:9076 2005:9077 2006:9072 2006:9073 2006:9074 2006:9075 2006:9076 2006:9077 2007:9072 2007:9073 2007:9074 2007:9075 2007:9076 2007:9077 2008:9072 2008:9073 2008:9074 2008:9075 2008:9076 2008:9077 2009:9072 2009:9073 2009:9074 2009:9075 2009:9076 2009:9077 2010:9072 2010:9073 2010:9074 2010:9075 2010:9076 2010:9077 2011:9072 2011:9073 2011:9074 2011:9075 2011:9076 2011:9077 2012:9072 2012:9073 2012:9074 2012:9075 2012:9076 2012:9077 1001:9078 1001:9079 1001:9080 1001:9081 1001:9082 1001:9083 1002:9078 1002:9079 1002:9080 1002:9081 1002:9082 1002:9083 1003:9078 1003:9079 1003:9080 1003:9081 1003:9082 1003:9083 1004:9078 1004:9079 1004:9080 1004:9081 1004:9082 1004:9083 1005:9078 1005:9079 1005:9080 1005:9081 1005:9082 1005:9083 1006:9078 1006:9079 1006:9080 1006:9081 1006:9082 1006:9083 1007:9078 1007:9079 1007:9080 1007:9081 1007:9082 1007:9083 1008:9078 1008:9079 1008:9080 1008:9081 1008:9082 1008:9083 1009:9078 1009:9079 1009:9080 1009:9081 1009:9082 1009:9083 1010:9078 1010:9079 1010:9080 1010:9081 1010:9082 1010:9083 1011:9078 1011:9079 1011:9080 1011:9081 1011:9082 1011:9083 1012:9078 1012:9079 1012:9080 1012:9081 1012:9082 1012:9083 1013:9078 1013:9079 1013:9080 1013:9081 1013:9082 1013:9083 1014:9078 1014:9079 1014:9080 1014:9081 1014:9082 1014:9083 1015:9078 1015:9079 1015:9080 1015:9081 1015:9082 1015:9083 1016:9078 1016:9079 1016:9080 1016:9081 1016:9082 1016:9083 2001:9078 2001:9079 2001:9080 2001:9081 2001:9082 2001:9083 2002:9078 2002:9079 2002:9080 2002:9081 2002:9082 2002:9083 2003:9078 2003:9079 2003:9080 2003:9081 2003:9082 2003:9083 2004:9078 2004:9079 2004:9080 2004:9081 2004:9082 2004:9083 2005:9078 2005:9079 2005:9080 2005:9081 2005:9082 2005:9083 2006:9078 2006:9079 2006:9080 2006:9081 2006:9082 2006:9083 2007:9078 2007:9079 2007:9080 2007:9081 2007:9082 2007:9083 2008:9078 2008:9079 2008:9080 2008:9081 2008:9082 2008:9083 2009:9078 2009:9079 2009:9080 2009:9081 2009:9082 2009:9083 2010:9078 2010:9079 2010:9080 2010:9081 2010:9082 2010:9083 2011:9078 2011:9079 2011:9080 2011:9081 2011:9082 2011:9083 2012:9078 2012:9079 2012:9080 2012:9081 2012:9082 2012:9083 1001:9084 1001:9085 1001:9086 1001:9087 1001:9088 1001:9089 1002:9084 1002:9085 1002:9086 1002:9087 1002:9088 1002:9089 1003:9084 1003:9085 1003:9086 1003:9087 1003:9088 1003:9089 1004:9084 1004:9085 1004:9086 1004:9087 1004:9088 1004:9089 1005:9084 1005:9085 1005:9086 1005:9087 1005:9088 1005:9089 1006:9084 1006:9085 1006:9086 1006:9087 1006:9088 1006:9089 1007:9084 1007:9085 1007:9086 1007:9087 1007:9088 1007:9089 1008:9084 1008:9085 1008:9086 1008:9087 1008:9088 1008:9089 1009:9084 1009:9085 1009:9086 1009:9087 1009:9088 1009:9089 1010:9084 1010:9085 1010:9086 1010:9087 1010:9088 1010:9089 1011:9084 1011:9085 1011:9086 1011:9087 1011:9088 1011:9089 1012:9084 1012:9085 1012:9086 1012:9087 1012:9088 1012:9089 1013:9084 1013:9085 1013:9086 1013:9087 1013:9088 1013:9089 1014:9084 1014:9085 1014:9086 1014:9087 1014:9088 1014:9089 1015:9084 1015:9085 1015:9086 1015:9087 1015:9088 1015:9089 1016:9084 1016:9085 1016:9086 1016:9087 1016:9088 1016:9089 2001:9084 2001:9085 2001:9086 2001:9087 2001:9088 2001:9089 2002:9084 2002:9085 2002:9086 2002:9087 2002:9088 2002:9089 2003:9084 2003:9085 2003:9086 2003:9087 2003:9088 2003:9089 2004:9084 2004:9085 2004:9086 2004:9087 2004:9088 2004:9089 2005:9084 2005:9085 2005:9086 2005:9087 2005:9088 2005:9089 2006:9084 2006:9085 2006:9086 2006:9087 2006:9088 2006:9089 2007:9084 2007:9085 2007:9086 2007:9087 2007:9088 2007:9089 2008:9084 2008:9085 2008:9086 2008:9087 2008:9088 2008:9089 2009:9084 2009:9085 2009:9086 2009:9087 2009:9088 2009:9089 2010:9084 2010:9085 2010:9086 2010:9087 2010:9088 2010:9089 2011:9084 2011:9085 2011:9086 2011:9087 2011:9088 2011:9089 2012:9084 2012:9085 2012:9086 2012:9087 2012:9088 2012:9089 1001:9090 1001:9091 1001:9092 1001:9093 1001:9094 1001:9095 1002:9090 1002:9091 1002:9092 1002:9093 1002:9094 1002:9095 1003:9090 1003:9091 1003:9092 1003:9093 1003:9094 1003:9095 1004:9090 1004:9091 1004:9092 1004:9093 1004:9094 1004:9095 1005:9090 1005:9091 1005:9092 1005:9093 1005:9094 1005:9095 1006:9090 1006:9091 1006:9092 1006:9093 1006:9094 1006:9095 1007:9090 1007:9091 1007:9092 1007:9093 1007:9094 1007:9095 1008:9090 1008:9091 1008:9092 1008:9093 1008:9094 1008:9095 1009:9090 1009:9091 1009:9092 1009:9093 1009:9094 1009:9095 1010:9090 1010:9091 1010:9092 1010:9093 1010:9094 1010:9095 1011:9090 1011:9091 1011:9092 1011:9093 1011:9094 1011:9095 1012:9090 1012:9091 1012:9092 1012:9093 1012:9094 1012:9095 1013:9090 1013:9091 1013:9092 1013:9093 1013:9094 1013:9095 1014:9090 1014:9091 1014:9092 1014:9093 1014:9094 1014:9095 1015:9090 1015:9091 1015:9092 1015:9093 1015:9094 1015:9095 1016:9090 1016:9091 1016:9092 1016:9093 1016:9094 1016:9095 2001:9090 2001:9091 2001:9092 2001:9093 2001:9094 2001:9095 2002:9090 2002:9091 2002:9092 2002:9093 2002:9094 2002:9095 2003:9090 2003:9091 2003:9092 2003:9093 2003:9094 2003:9095 2004:9090 2004:9091 2004:9092 2004:9093 2004:9094 2004:9095 2005:9090 2005:9091 2005:9092 2005:9093 2005:9094 2005:9095 2006:9090 2006:9091 2006:9092 2006:9093 2006:9094 2006:9095 2007:9090 2007:9091 2007:9092 2007:9093 2007:9094 2007:9095 2008:9090 2008:9091 2008:9092 2008:9093 2008:9094 2008:9095 2009:9090 2009:9091 2009:9092 2009:9093 2009:9094 2009:9095 2010:9090 2010:9091 2010:9092 2010:9093 2010:9094 2010:9095 2011:9090 2011:9091 2011:9092 2011:9093 2011:9094 2011:9095 2012:9090 2012:9091 2012:9092 2012:9093 2012:9094 2012:9095 1001:9096 1001:9097 1001:9098 1001:9099 1001:9100 1001:9101 1002:9096 1002:9097 1002:9098 1002:9099 1002:9100 1002:9101 1003:9096 1003:9097 1003:9098 1003:9099 1003:9100 1003:9101 1004:9096 1004:9097 1004:9098 1004:9099 1004:9100 1004:9101 1005:9096 1005:9097 1005:9098 1005:9099 1005:9100 1005:9101 1006:9096 1006:9097 1006:9098 1006:9099 1006:9100 1006:9101 1007:9096 1007:9097 1007:9098 1007:9099 1007:9100 1007:9101 1008:9096 1008:9097 1008:9098 1008:9099 1008:9100 1008:9101 1009:9096 1009:9097 1009:9098 1009:9099 1009:9100 1009:9101 1010:9096 1010:9097 1010:9098 1010:9099 1010:9100 1010:9101 1011:9096 1011:9097 1011:9098 1011:9099 1011:9100 1011:9101 1012:9096 1012:9097 1012:9098 1012:9099 1012:9100 1012:9101 1013:9096 1013:9097 1013:9098 1013:9099 1013:9100 1013:9101 1014:9096 1014:9097 1014:9098 1014:9099 1014:9100 1014:9101 1015:9096 1015:9097 1015:9098 1015:9099 1015:9100 1015:9101 1016:9096 1016:9097 1016:9098 1016:9099 1016:9100 1016:9101 2001:9096 2001:9097 2001:9098 2001:9099 2001:9100 2001:9101 2002:9096 2002:9097 2002:9098 2002:9099 2002:9100 2002:9101 2003:9096 2003:9097 2003:9098 2003:9099 2003:9100 2003:9101 2004:9096 2004:9097 2004:9098 2004:9099 2004:9100 2004:9101 2005:9096 2005:9097 2005:9098 2005:9099 2005:9100 2005:9101 2006:9096 2006:9097 2006:9098 2006:9099 2006:9100 2006:9101 2007:9096 2007:9097 2007:9098 2007:9099 2007:9100 2007:9101 2008:9096 2008:9097 2008:9098 2008:9099 2008:9100 2008:9101 2009:9096 2009:9097 2009:9098 2009:9099 2009:9100 2009:9101 2010:9096 2010:9097 2010:9098 2010:9099 2010:9100 2010:9101 2011:9096 2011:9097 2011:9098 2011:9099 2011:9100 2011:9101 2012:9096 2012:9097 2012:9098 2012:9099 2012:9100 2012:9101 1001:9102 1001:9103 1001:9104 1001:9105 — — 1002:9102 1002:9103 1002:9104 1002:9105 1003:9102 1003:9103 1003:9104 1003:9105 1004:9102 1004:9103 1004:9104 1004:9105 1005:9102 1005:9103 1005:9104 1005:9105 1006:9102 1006:9103 1006:9104 1006:9105 1007:9102 1007:9103 1007:9104 1007:9105 1008:9102 1008:9103 1008:9104 1008:9105 1009:9102 1009:9103 1009:9104 1009:9105 1010:9102 1010:9103 1010:9104 1010:9105 1011:9102 1011:9103 1011:9104 1011:9105 1012:9102 1012:9103 1012:9104 1012:9105 1013:9102 1013:9103 1013:9104 1013:9105 1014:9102 1014:9103 1014:9104 1014:9105 1015:9102 1015:9103 1015:9104 1015:9105 1016:9102 1016:9103 1016:9104 1016:9105 2001:9102 2001:9103 2001:9104 2001:9105 2002:9102 2002:9103 2002:9104 2002:9105 2003:9102 2003:9103 2003:9104 2003:9105 2004:9102 2004:9103 2004:9104 2004:9105 2005:9102 2005:9103 2005:9104 2005:9105 2006:9102 2006:9103 2006:9104 2006:9105 2007:9102 2007:9103 2007:9104 2007:9105 2008:9102 2008:9103 2008:9104 2008:9105 2009:9102 2009:9103 2009:9104 2009:9105 2010:9102 2010:9103 2010:9104 2010:9105 2011:9102 2011:9103 2011:9104 2011:9105 2012:9102 2012:9103 2012:9104 2012:9105

TABLE B Example combinations of a compound X with a compound Y. X:Y X:Y X:Y X:Y X:Y X:Y 3001:9000 3001:9001 3001:9002 3001:9003 3001:9004 3001:9005 3002:9000 3002:9001 3002:9002 3002:9003 3002:9004 3002:9005 3003:9000 3003:9001 3003:9002 3003:9003 3003:9004 3003:9005 3004:9000 3004:9001 3004:9002 3004:9003 3004:9004 3004:9005 3005:9000 3005:9001 3005:9002 3005:9003 3005:9004 3005:9005 3006:9000 3006:9001 3006:9002 3006:9003 3006:9004 3006:9005 3007:9000 3007:9001 3007:9002 3007:9003 3007:9004 3007:9005 3008:9000 3008:9001 3008:9002 3008:9003 3008:9004 3008:9005 3009:9000 3009:9001 3009:9002 3009:9003 3009:9004 3009:9005 3010:9000 3010:9001 3010:9002 3010:9003 3010:9004 3010:9005 3011:9000 3011:9001 3011:9002 3011:9003 3011:9004 3011:9005 3012:9000 3012:9001 3012:9002 3012:9003 3012:9004 3012:9005 3013:9000 3013:9001 3013:9002 3013:9003 3013:9004 3013:9005 3014:9000 3014:9001 3014:9002 3014:9003 3014:9004 3014:9005 4001:9000 4001:9001 4001:9002 4001:9003 4001:9004 4001:9005 4002:9000 4002:9001 4002:9002 4002:9003 4002:9004 4002:9005 4003:9000 4003:9001 4003:9002 4003:9003 4003:9004 4003:9005 4004:9000 4004:9001 4004:9002 4004:9003 4004:9004 4004:9005 4005:9000 4005:9001 4005:9002 4005:9003 4005:9004 4005:9005 4006:9000 4006:9001 4006:9002 4006:9003 4006:9004 4006:9005 4007:9000 4007:9001 4007:9002 4007:9003 4007:9004 4007:9005 4008:9000 4008:9001 4008:9002 4008:9003 4008:9004 4008:9005 4009:9000 4009:9001 4009:9002 4009:9003 4009:9004 4009:9005 4010:9000 4010:9001 4010:9002 4010:9003 4010:9004 4010:9005 4011:9000 4011:9001 4011:9002 4011:9003 4011:9004 4011:9005 4012:9000 4012:9001 4012:9002 4012:9003 4012:9004 4012:9005 5001:9000 5001:9001 5001:9002 5001:9003 5001:9004 5001:9005 5002:9000 5002:9001 5002:9002 5002:9003 5002:9004 5002:9005 5003:9000 5003:9001 5003:9002 5003:9003 5003:9004 5003:9005 5004:9000 5004:9001 5004:9002 5004:9003 5004:9004 5004:9005 5005:9000 5005:9001 5005:9002 5005:9003 5005:9004 5005:9005 5006:9000 5006:9001 5006:9002 5006:9003 5006:9004 5006:9005 5007:9000 5007:9001 5007:9002 5007:9003 5007:9004 5007:9005 5008:9000 5008:9001 5008:9002 5008:9003 5008:9004 5008:9005 5009:9000 5009:9001 5009:9002 5009:9003 5009:9004 5009:9005 5010:9000 5010:9001 5010:9002 5010:9003 5010:9004 5010:9005 5011:9000 5011:9001 5011:9002 5011:9003 5011:9004 5011:9005 5012:9000 5012:9001 5012:9002 5012:9003 5012:9004 5012:9005 3001:9006 3001:9007 3001:9008 3001:9009 3001:9010 3001:9011 3002:9006 3002:9007 3002:9008 3002:9009 3002:9010 3002:9011 3003:9006 3003:9007 3003:9008 3003:9009 3003:9010 3003:9011 3004:9006 3004:9007 3004:9008 3004:9009 3004:9010 3004:9011 3005:9006 3005:9007 3005:9008 3005:9009 3005:9010 3005:9011 3006:9006 3006:9007 3006:9008 3006:9009 3006:9010 3006:9011 3007:9006 3007:9007 3007:9008 3007:9009 3007:9010 3007:9011 3008:9006 3008:9007 3008:9008 3008:9009 3008:9010 3008:9011 3009:9006 3009:9007 3009:9008 3009:9009 3009:9010 3009:9011 3010:9006 3010:9007 3010:9008 3010:9009 3010:9010 3010:9011 3011:9006 3011:9007 3011:9008 3011:9009 3011:9010 3011:9011 3012:9006 3012:9007 3012:9008 3012:9009 3012:9010 3012:9011 3013:9006 3013:9007 3013:9008 3013:9009 3013:9010 3013:9011 3014:9006 3014:9007 3014:9008 3014:9009 3014:9010 3014:9011 4001:9006 4001:9007 4001:9008 4001:9009 4001:9010 4001:9011 4002:9006 4002:9007 4002:9008 4002:9009 4002:9010 4002:9011 4003:9006 4003:9007 4003:9008 4003:9009 4003:9010 4003:9011 4004:9006 4004:9007 4004:9008 4004:9009 4004:9010 4004:9011 4005:9006 4005:9007 4005:9008 4005:9009 4005:9010 4005:9011 4006:9006 4006:9007 4006:9008 4006:9009 4006:9010 4006:9011 4007:9006 4007:9007 4007:9008 4007:9009 4007:9010 4007:9011 4008:9006 4008:9007 4008:9008 4008:9009 4008:9010 4008:9011 4009:9006 4009:9007 4009:9008 4009:9009 4009:9010 4009:9011 4010:9006 4010:9007 4010:9008 4010:9009 4010:9010 4010:9011 4011:9006 4011:9007 4011:9008 4011:9009 4011:9010 4011:9011 4012:9006 4012:9007 4012:9008 4012:9009 4012:9010 4012:9011 5001:9006 5001:9007 5001:9008 5001:9009 5001:9010 5001:9011 5002:9006 5002:9007 5002:9008 5002:9009 5002:9010 5002:9011 5003:9006 5003:9007 5003:9008 5003:9009 5003:9010 5003:9011 5004:9006 5004:9007 5004:9008 5004:9009 5004:9010 5004:9011 5005:9006 5005:9007 5005:9008 5005:9009 5005:9010 5005:9011 5006:9006 5006:9007 5006:9008 5006:9009 5006:9010 5006:9011 5007:9006 5007:9007 5007:9008 5007:9009 5007:9010 5007:9011 5008:9006 5008:9007 5008:9008 5008:9009 5008:9010 5008:9011 5009:9006 5009:9007 5009:9008 5009:9009 5009:9010 5009:9011 5010:9006 5010:9007 5010:9008 5010:9009 5010:9010 5010:9011 5011:9006 5011:9007 5011:9008 5011:9009 5011:9010 5011:9011 5012:9006 5012:9007 5012:9008 5012:9009 5012:9010 5012:9011 3001:9012 3001:9013 3001:9014 3001:9015 3001:9016 3001:9017 3002:9012 3002:9013 3002:9014 3002:9015 3002:9016 3002:9017 3003:9012 3003:9013 3003:9014 3003:9015 3003:9016 3003:9017 3004:9012 3004:9013 3004:9014 3004:9015 3004:9016 3004:9017 3005:9012 3005:9013 3005:9014 3005:9015 3005:9016 3005:9017 3006:9012 3006:9013 3006:9014 3006:9015 3006:9016 3006:9017 3007:9012 3007:9013 3007:9014 3007:9015 3007:9016 3007:9017 3008:9012 3008:9013 3008:9014 3008:9015 3008:9016 3008:9017 3009:9012 3009:9013 3009:9014 3009:9015 3009:9016 3009:9017 3010:9012 3010:9013 3010:9014 3010:9015 3010:9016 3010:9017 3011:9012 3011:9013 3011:9014 3011:9015 3011:9016 3011:9017 3012:9012 3012:9013 3012:9014 3012:9015 3012:9016 3012:9017 3013:9012 3013:9013 3013:9014 3013:9015 3013:9016 3013:9017 3014:9012 3014:9013 3014:9014 3014:9015 3014:9016 3014:9017 4001:9012 4001:9013 4001:9014 4001:9015 4001:9016 4001:9017 4002:9012 4002:9013 4002:9014 4002:9015 4002:9016 4002:9017 4003:9012 4003:9013 4003:9014 4003:9015 4003:9016 4003:9017 4004:9012 4004:9013 4004:9014 4004:9015 4004:9016 4004:9017 4005:9012 4005:9013 4005:9014 4005:9015 4005:9016 4005:9017 4006:9012 4006:9013 4006:9014 4006:9015 4006:9016 4006:9017 4007:9012 4007:9013 4007:9014 4007:9015 4007:9016 4007:9017 4008:9012 4008:9013 4008:9014 4008:9015 4008:9016 4008:9017 4009:9012 4009:9013 4009:9014 4009:9015 4009:9016 4009:9017 4010:9012 4010:9013 4010:9014 4010:9015 4010:9016 4010:9017 4011:9012 4011:9013 4011:9014 4011:9015 4011:9016 4011:9017 4012:9012 4012:9013 4012:9014 4012:9015 4012:9016 4012:9017 5001:9012 5001:9013 5001:9014 5001:9015 5001:9016 5001:9017 5002:9012 5002:9013 5002:9014 5002:9015 5002:9016 5002:9017 5003:9012 5003:9013 5003:9014 5003:9015 5003:9016 5003:9017 5004:9012 5004:9013 5004:9014 5004:9015 5004:9016 5004:9017 5005:9012 5005:9013 5005:9014 5005:9015 5005:9016 5005:9017 5006:9012 5006:9013 5006:9014 5006:9015 5006:9016 5006:9017 5007:9012 5007:9013 5007:9014 5007:9015 5007:9016 5007:9017 5008:9012 5008:9013 5008:9014 5008:9015 5008:9016 5008:9017 5009:9012 5009:9013 5009:9014 5009:9015 5009:9016 5009:9017 5010:9012 5010:9013 5010:9014 5010:9015 5010:9016 5010:9017 5011:9012 5011:9013 5011:9014 5011:9015 5011:9016 5011:9017 5012:9012 5012:9013 5012:9014 5012:9015 5012:9016 5012:9017 3001:9018 3001:9019 3001:9020 3001:9021 3001:9022 3001:9023 3002:9018 3002:9019 3002:9020 3002:9021 3002:9022 3002:9023 3003:9018 3003:9019 3003:9020 3003:9021 3003:9022 3003:9023 3004:9018 3004:9019 3004:9020 3004:9021 3004:9022 3004:9023 3005:9018 3005:9019 3005:9020 3005:9021 3005:9022 3005:9023 3006:9018 3006:9019 3006:9020 3006:9021 3006:9022 3006:9023 3007:9018 3007:9019 3007:9020 3007:9021 3007:9022 3007:9023 3008:9018 3008:9019 3008:9020 3008:9021 3008:9022 3008:9023 3009:9018 3009:9019 3009:9020 3009:9021 3009:9022 3009:9023 3010:9018 3010:9019 3010:9020 3010:9021 3010:9022 3010:9023 3011:9018 3011:9019 3011:9020 3011:9021 3011:9022 3011:9023 3012:9018 3012:9019 3012:9020 3012:9021 3012:9022 3012:9023 3013:9018 3013:9019 3013:9020 3013:9021 3013:9022 3013:9023 3014:9018 3014:9019 3014:9020 3014:9021 3014:9022 3014:9023 4001:9018 4001:9019 4001:9020 4001:9021 4001:9022 4001:9023 4002:9018 4002:9019 4002:9020 4002:9021 4002:9022 4002:9023 4003:9018 4003:9019 4003:9020 4003:9021 4003:9022 4003:9023 4004:9018 4004:9019 4004:9020 4004:9021 4004:9022 4004:9023 4005:9018 4005:9019 4005:9020 4005:9021 4005:9022 4005:9023 4006:9018 4006:9019 4006:9020 4006:9021 4006:9022 4006:9023 4007:9018 4007:9019 4007:9020 4007:9021 4007:9022 4007:9023 4008:9018 4008:9019 4008:9020 4008:9021 4008:9022 4008:9023 4009:9018 4009:9019 4009:9020 4009:9021 4009:9022 4009:9023 4010:9018 4010:9019 4010:9020 4010:9021 4010:9022 4010:9023 4011:9018 4011:9019 4011:9020 4011:9021 4011:9022 4011:9023 4012:9018 4012:9019 4012:9020 4012:9021 4012:9022 4012:9023 5001:9018 5001:9019 5001:9020 5001:9021 5001:9022 5001:9023 5002:9018 5002:9019 5002:9020 5002:9021 5002:9022 5002:9023 5003:9018 5003:9019 5003:9020 5003:9021 5003:9022 5003:9023 5004:9018 5004:9019 5004:9020 5004:9021 5004:9022 5004:9023 5005:9018 5005:9019 5005:9020 5005:9021 5005:9022 5005:9023 5006:9018 5006:9019 5006:9020 5006:9021 5006:9022 5006:9023 5007:9018 5007:9019 5007:9020 5007:9021 5007:9022 5007:9023 5008:9018 5008:9019 5008:9020 5008:9021 5008:9022 5008:9023 5009:9018 5009:9019 5009:9020 5009:9021 5009:9022 5009:9023 5010:9018 5010:9019 5010:9020 5010:9021 5010:9022 5010:9023 5011:9018 5011:9019 5011:9020 5011:9021 5011:9022 5011:9023 5012:9018 5012:9019 5012:9020 5012:9021 5012:9022 5012:9023 3001:9024 3001:9025 3001:9026 3001:9027 3001:9028 3001:9029 3002:9024 3002:9025 3002:9026 3002:9027 3002:9028 3002:9029 3003:9024 3003:9025 3003:9026 3003:9027 3003:9028 3003:9029 3004:9024 3004:9025 3004:9026 3004:9027 3004:9028 3004:9029 3005:9024 3005:9025 3005:9026 3005:9027 3005:9028 3005:9029 3006:9024 3006:9025 3006:9026 3006:9027 3006:9028 3006:9029 3007:9024 3007:9025 3007:9026 3007:9027 3007:9028 3007:9029 3008:9024 3008:9025 3008:9026 3008:9027 3008:9028 3008:9029 3009:9024 3009:9025 3009:9026 3009:9027 3009:9028 3009:9029 3010:9024 3010:9025 3010:9026 3010:9027 3010:9028 3010:9029 3011:9024 3011:9025 3011:9026 3011:9027 3011:9028 3011:9029 3012:9024 3012:9025 3012:9026 3012:9027 3012:9028 3012:9029 3013:9024 3013:9025 3013:9026 3013:9027 3013:9028 3013:9029 3014:9024 3014:9025 3014:9026 3014:9027 3014:9028 3014:9029 4001:9024 4001:9025 4001:9026 4001:9027 4001:9028 4001:9029 4002:9024 4002:9025 4002:9026 4002:9027 4002:9028 4002:9029 4003:9024 4003:9025 4003:9026 4003:9027 4003:9028 4003:9029 4004:9024 4004:9025 4004:9026 4004:9027 4004:9028 4004:9029 4005:9024 4005:9025 4005:9026 4005:9027 4005:9028 4005:9029 4006:9024 4006:9025 4006:9026 4006:9027 4006:9028 4006:9029 4007:9024 4007:9025 4007:9026 4007:9027 4007:9028 4007:9029 4008:9024 4008:9025 4008:9026 4008:9027 4008:9028 4008:9029 4009:9024 4009:9025 4009:9026 4009:9027 4009:9028 4009:9029 4010:9024 4010:9025 4010:9026 4010:9027 4010:9028 4010:9029 4011:9024 4011:9025 4011:9026 4011:9027 4011:9028 4011:9029 4012:9024 4012:9025 4012:9026 4012:9027 4012:9028 4012:9029 5001:9024 5001:9025 5001:9026 5001:9027 5001:9028 5001:9029 5002:9024 5002:9025 5002:9026 5002:9027 5002:9028 5002:9029 5003:9024 5003:9025 5003:9026 5003:9027 5003:9028 5003:9029 5004:9024 5004:9025 5004:9026 5004:9027 5004:9028 5004:9029 5005:9024 5005:9025 5005:9026 5005:9027 5005:9028 5005:9029 5006:9024 5006:9025 5006:9026 5006:9027 5006:9028 5006:9029 5007:9024 5007:9025 5007:9026 5007:9027 5007:9028 5007:9029 5008:9024 5008:9025 5008:9026 5008:9027 5008:9028 5008:9029 5009:9024 5009:9025 5009:9026 5009:9027 5009:9028 5009:9029 5010:9024 5010:9025 5010:9026 5010:9027 5010:9028 5010:9029 5011:9024 5011:9025 5011:9026 5011:9027 5011:9028 5011:9029 5012:9024 5012:9025 5012:9026 5012:9027 5012:9028 5012:9029 3001:9030 3001:9031 3001:9032 3001:9033 3001:9034 3001:9035 3002:9030 3002:9031 3002:9032 3002:9033 3002:9034 3002:9035 3003:9030 3003:9031 3003:9032 3003:9033 3003:9034 3003:9035 3004:9030 3004:9031 3004:9032 3004:9033 3004:9034 3004:9035 3005:9030 3005:9031 3005:9032 3005:9033 3005:9034 3005:9035 3006:9030 3006:9031 3006:9032 3006:9033 3006:9034 3006:9035 3007:9030 3007:9031 3007:9032 3007:9033 3007:9034 3007:9035 3008:9030 3008:9031 3008:9032 3008:9033 3008:9034 3008:9035 3009:9030 3009:9031 3009:9032 3009:9033 3009:9034 3009:9035 3010:9030 3010:9031 3010:9032 3010:9033 3010:9034 3010:9035 3011:9030 3011:9031 3011:9032 3011:9033 3011:9034 3011:9035 3012:9030 3012:9031 3012:9032 3012:9033 3012:9034 3012:9035 3013:9030 3013:9031 3013:9032 3013:9033 3013:9034 3013:9035 3014:9030 3014:9031 3014:9032 3014:9033 3014:9034 3014:9035 4001:9030 4001:9031 4001:9032 4001:9033 4001:9034 4001:9035 4002:9030 4002:9031 4002:9032 4002:9033 4002:9034 4002:9035 4003:9030 4003:9031 4003:9032 4003:9033 4003:9034 4003:9035 4004:9030 4004:9031 4004:9032 4004:9033 4004:9034 4004:9035 4005:9030 4005:9031 4005:9032 4005:9033 4005:9034 4005:9035 4006:9030 4006:9031 4006:9032 4006:9033 4006:9034 4006:9035 4007:9030 4007:9031 4007:9032 4007:9033 4007:9034 4007:9035 4008:9030 4008:9031 4008:9032 4008:9033 4008:9034 4008:9035 4009:9030 4009:9031 4009:9032 4009:9033 4009:9034 4009:9035 4010:9030 4010:9031 4010:9032 4010:9033 4010:9034 4010:9035 4011:9030 4011:9031 4011:9032 4011:9033 4011:9034 4011:9035 4012:9030 4012:9031 4012:9032 4012:9033 4012:9034 4012:9035 5001:9030 5001:9031 5001:9032 5001:9033 5001:9034 5001:9035 5002:9030 5002:9031 5002:9032 5002:9033 5002:9034 5002:9035 5003:9030 5003:9031 5003:9032 5003:9033 5003:9034 5003:9035 5004:9030 5004:9031 5004:9032 5004:9033 5004:9034 5004:9035 5005:9030 5005:9031 5005:9032 5005:9033 5005:9034 5005:9035 5006:9030 5006:9031 5006:9032 5006:9033 5006:9034 5006:9035 5007:9030 5007:9031 5007:9032 5007:9033 5007:9034 5007:9035 5008:9030 5008:9031 5008:9032 5008:9033 5008:9034 5008:9035 5009:9030 5009:9031 5009:9032 5009:9033 5009:9034 5009:9035 5010:9030 5010:9031 5010:9032 5010:9033 5010:9034 5010:9035 5011:9030 5011:9031 5011:9032 5011:9033 5011:9034 5011:9035 5012:9030 5012:9031 5012:9032 5012:9033 5012:9034 5012:9035 3001:9036 3001:9037 3001:9038 3001:9039 3001:9040 3001:9041 3002:9036 3002:9037 3002:9038 3002:9039 3002:9040 3002:9041 3003:9036 3003:9037 3003:9038 3003:9039 3003:9040 3003:9041 3004:9036 3004:9037 3004:9038 3004:9039 3004:9040 3004:9041 3005:9036 3005:9037 3005:9038 3005:9039 3005:9040 3005:9041 3006:9036 3006:9037 3006:9038 3006:9039 3006:9040 3006:9041 3007:9036 3007:9037 3007:9038 3007:9039 3007:9040 3007:9041 3008:9036 3008:9037 3008:9038 3008:9039 3008:9040 3008:9041 3009:9036 3009:9037 3009:9038 3009:9039 3009:9040 3009:9041 3010:9036 3010:9037 3010:9038 3010:9039 3010:9040 3010:9041 3011:9036 3011:9037 3011:9038 3011:9039 3011:9040 3011:9041 3012:9036 3012:9037 3012:9038 3012:9039 3012:9040 3012:9041 3013:9036 3013:9037 3013:9038 3013:9039 3013:9040 3013:9041 3014:9036 3014:9037 3014:9038 3014:9039 3014:9040 3014:9041 4001:9036 4001:9037 4001:9038 4001:9039 4001:9040 4001:9041 4002:9036 4002:9037 4002:9038 4002:9039 4002:9040 4002:9041 4003:9036 4003:9037 4003:9038 4003:9039 4003:9040 4003:9041 4004:9036 4004:9037 4004:9038 4004:9039 4004:9040 4004:9041 4005:9036 4005:9037 4005:9038 4005:9039 4005:9040 4005:9041 4006:9036 4006:9037 4006:9038 4006:9039 4006:9040 4006:9041 4007:9036 4007:9037 4007:9038 4007:9039 4007:9040 4007:9041 4008:9036 4008:9037 4008:9038 4008:9039 4008:9040 4008:9041 4009:9036 4009:9037 4009:9038 4009:9039 4009:9040 4009:9041 4010:9036 4010:9037 4010:9038 4010:9039 4010:9040 4010:9041 4011:9036 4011:9037 4011:9038 4011:9039 4011:9040 4011:9041 4012:9036 4012:9037 4012:9038 4012:9039 4012:9040 4012:9041 5001:9036 5001:9037 5001:9038 5001:9039 5001:9040 5001:9041 5002:9036 5002:9037 5002:9038 5002:9039 5002:9040 5002:9041 5003:9036 5003:9037 5003:9038 5003:9039 5003:9040 5003:9041 5004:9036 5004:9037 5004:9038 5004:9039 5004:9040 5004:9041 5005:9036 5005:9037 5005:9038 5005:9039 5005:9040 5005:9041 5006:9036 5006:9037 5006:9038 5006:9039 5006:9040 5006:9041 5007:9036 5007:9037 5007:9038 5007:9039 5007:9040 5007:9041 5008:9036 5008:9037 5008:9038 5008:9039 5008:9040 5008:9041 5009:9036 5009:9037 5009:9038 5009:9039 5009:9040 5009:9041 5010:9036 5010:9037 5010:9038 5010:9039 5010:9040 5010:9041 5011:9036 5011:9037 5011:9038 5011:9039 5011:9040 5011:9041 5012:9036 5012:9037 5012:9038 5012:9039 5012:9040 5012:9041 3001:9042 3001:9043 3001:9044 3001:9045 3001:9046 3001:9047 3002:9042 3002:9043 3002:9044 3002:9045 3002:9046 3002:9047 3003:9042 3003:9043 3003:9044 3003:9045 3003:9046 3003:9047 3004:9042 3004:9043 3004:9044 3004:9045 3004:9046 3004:9047 3005:9042 3005:9043 3005:9044 3005:9045 3005:9046 3005:9047 3006:9042 3006:9043 3006:9044 3006:9045 3006:9046 3006:9047 3007:9042 3007:9043 3007:9044 3007:9045 3007:9046 3007:9047 3008:9042 3008:9043 3008:9044 3008:9045 3008:9046 3008:9047 3009:9042 3009:9043 3009:9044 3009:9045 3009:9046 3009:9047 3010:9042 3010:9043 3010:9044 3010:9045 3010:9046 3010:9047 3011:9042 3011:9043 3011:9044 3011:9045 3011:9046 3011:9047 3012:9042 3012:9043 3012:9044 3012:9045 3012:9046 3012:9047 3013:9042 3013:9043 3013:9044 3013:9045 3013:9046 3013:9047 3014:9042 3014:9043 3014:9044 3014:9045 3014:9046 3014:9047 4001:9042 4001:9043 4001:9044 4001:9045 4001:9046 4001:9047 4002:9042 4002:9043 4002:9044 4002:9045 4002:9046 4002:9047 4003:9042 4003:9043 4003:9044 4003:9045 4003:9046 4003:9047 4004:9042 4004:9043 4004:9044 4004:9045 4004:9046 4004:9047 4005:9042 4005:9043 4005:9044 4005:9045 4005:9046 4005:9047 4006:9042 4006:9043 4006:9044 4006:9045 4006:9046 4006:9047 4007:9042 4007:9043 4007:9044 4007:9045 4007:9046 4007:9047 4008:9042 4008:9043 4008:9044 4008:9045 4008:9046 4008:9047 4009:9042 4009:9043 4009:9044 4009:9045 4009:9046 4009:9047 4010:9042 4010:9043 4010:9044 4010:9045 4010:9046 4010:9047 4011:9042 4011:9043 4011:9044 4011:9045 4011:9046 4011:9047 4012:9042 4012:9043 4012:9044 4012:9045 4012:9046 4012:9047 5001:9042 5001:9043 5001:9044 5001:9045 5001:9046 5001:9047 5002:9042 5002:9043 5002:9044 5002:9045 5002:9046 5002:9047 5003:9042 5003:9043 5003:9044 5003:9045 5003:9046 5003:9047 5004:9042 5004:9043 5004:9044 5004:9045 5004:9046 5004:9047 5005:9042 5005:9043 5005:9044 5005:9045 5005:9046 5005:9047 5006:9042 5006:9043 5006:9044 5006:9045 5006:9046 5006:9047 5007:9042 5007:9043 5007:9044 5007:9045 5007:9046 5007:9047 5008:9042 5008:9043 5008:9044 5008:9045 5008:9046 5008:9047 5009:9042 5009:9043 5009:9044 5009:9045 5009:9046 5009:9047 5010:9042 5010:9043 5010:9044 5010:9045 5010:9046 5010:9047 5011:9042 5011:9043 5011:9044 5011:9045 5011:9046 5011:9047 5012:9042 5012:9043 5012:9044 5012:9045 5012:9046 5012:9047 3001:9048 3001:9049 3001:9050 3001:9051 3001:9052 3001:9053 3002:9048 3002:9049 3002:9050 3002:9051 3002:9052 3002:9053 3003:9048 3003:9049 3003:9050 3003:9051 3003:9052 3003:9053 3004:9048 3004:9049 3004:9050 3004:9051 3004:9052 3004:9053 3005:9048 3005:9049 3005:9050 3005:9051 3005:9052 3005:9053 3006:9048 3006:9049 3006:9050 3006:9051 3006:9052 3006:9053 3007:9048 3007:9049 3007:9050 3007:9051 3007:9052 3007:9053 3008:9048 3008:9049 3008:9050 3008:9051 3008:9052 3008:9053 3009:9048 3009:9049 3009:9050 3009:9051 3009:9052 3009:9053 3010:9048 3010:9049 3010:9050 3010:9051 3010:9052 3010:9053 3011:9048 3011:9049 3011:9050 3011:9051 3011:9052 3011:9053 3012:9048 3012:9049 3012:9050 3012:9051 3012:9052 3012:9053 3013:9048 3013:9049 3013:9050 3013:9051 3013:9052 3013:9053 3014:9048 3014:9049 3014:9050 3014:9051 3014:9052 3014:9053 4001:9048 4001:9049 4001:9050 4001:9051 4001:9052 4001:9053 4002:9048 4002:9049 4002:9050 4002:9051 4002:9052 4002:9053 4003:9048 4003:9049 4003:9050 4003:9051 4003:9052 4003:9053 4004:9048 4004:9049 4004:9050 4004:9051 4004:9052 4004:9053 4005:9048 4005:9049 4005:9050 4005:9051 4005:9052 4005:9053 4006:9048 4006:9049 4006:9050 4006:9051 4006:9052 4006:9053 4007:9048 4007:9049 4007:9050 4007:9051 4007:9052 4007:9053 4008:9048 4008:9049 4008:9050 4008:9051 4008:9052 4008:9053 4009:9048 4009:9049 4009:9050 4009:9051 4009:9052 4009:9053 4010:9048 4010:9049 4010:9050 4010:9051 4010:9052 4010:9053 4011:9048 4011:9049 4011:9050 4011:9051 4011:9052 4011:9053 4012:9048 4012:9049 4012:9050 4012:9051 4012:9052 4012:9053 5001:9048 5001:9049 5001:9050 5001:9051 5001:9052 5001:9053 5002:9048 5002:9049 5002:9050 5002:9051 5002:9052 5002:9053 5003:9048 5003:9049 5003:9050 5003:9051 5003:9052 5003:9053 5004:9048 5004:9049 5004:9050 5004:9051 5004:9052 5004:9053 5005:9048 5005:9049 5005:9050 5005:9051 5005:9052 5005:9053 5006:9048 5006:9049 5006:9050 5006:9051 5006:9052 5006:9053 5007:9048 5007:9049 5007:9050 5007:9051 5007:9052 5007:9053 5008:9048 5008:9049 5008:9050 5008:9051 5008:9052 5008:9053 5009:9048 5009:9049 5009:9050 5009:9051 5009:9052 5009:9053 5010:9048 5010:9049 5010:9050 5010:9051 5010:9052 5010:9053 5011:9048 5011:9049 5011:9050 5011:9051 5011:9052 5011:9053 5012:9048 5012:9049 5012:9050 5012:9051 5012:9051 5012:9053 3001:9054 3001:9055 3001:9056 3001:9057 3001:9058 3001:9059 3002:9054 3002:9055 3002:9056 3002:9057 3002:9058 3002:9059 3003:9054 3003:9055 3003:9056 3003:9057 3003:9058 3003:9059 3004:9054 3004:9055 3004:9056 3004:9057 3004:9058 3004:9059 3005:9054 3005:9055 3005:9056 3005:9057 3005:9058 3005:9059 3006:9054 3006:9055 3006:9056 3006:9057 3006:9058 3006:9059 3007:9054 3007:9055 3007:9056 3007:9057 3007:9058 3007:9059 3008:9054 3008:9055 3008:9056 3008:9057 3008:9058 3008:9059 3009:9054 3009:9055 3009:9056 3009:9057 3009:9058 3009:9059 3010:9054 3010:9055 3010:9056 3010:9057 3010:9058 3010:9059 3011:9054 3011:9055 3011:9056 3011:9057 3011:9058 3011:9059 3012:9054 3012:9055 3012:9056 3012:9057 3012:9058 3012:9059 3013:9054 3013:9055 3013:9056 3013:9057 3013:9058 3013:9059 3014:9054 3014:9055 3014:9056 3014:9057 3014:9058 3014:9059 4001:9054 4001:9055 4001:9056 4001:9057 4001:9058 4001:9059 4002:9054 4002:9055 4002:9056 4002:9057 4002:9058 4002:9059 4003:9054 4003:9055 4003:9056 4003:9057 4003:9058 4003:9059 4004:9054 4004:9055 4004:9056 4004:9057 4004:9058 4004:9059 4005:9054 4005:9055 4005:9056 4005:9057 4005:9058 4005:9059 4006:9054 4006:9055 4006:9056 4006:9057 4006:9058 4006:9059 4007:9054 4007:9055 4007:9056 4007:9057 4007:9058 4007:9059 4008:9054 4008:9055 4008:9056 4008:9057 4008:9058 4008:9059 4009:9054 4009:9055 4009:9056 4009:9057 4009:9058 4009:9059 4010:9054 4010:9055 4010:9056 4010:9057 4010:9058 4010:9059 4011:9054 4011:9055 4011:9056 4011:9057 4011:9058 4011:9059 4012:9054 4012:9055 4012:9056 4012:9057 4012:9058 4012:9059 5001:9054 5001:9055 5001:9056 5001:9057 5001:9058 5001:9059 5002:9054 5002:9055 5002:9056 5002:9057 5002:9058 5002:9059 5003:9054 5003:9055 5003:9056 5003:9057 5003:9058 5003:9059 5004:9054 5004:9055 5004:9056 5004:9057 5004:9058 5004:9059 5005:9054 5005:9055 5005:9056 5005:9057 5005:9058 5005:9059 5006:9054 5006:9055 5006:9056 5006:9057 5006:9058 5006:9059 5007:9054 5007:9055 5007:9056 5007:9057 5007:9058 5007:9059 5008:9054 5008:9055 5008:9056 5008:9057 5008:9058 5008:9059 5009:9054 5009:9055 5009:9056 5009:9057 5009:9058 5009:9059 5010:9054 5010:9055 5010:9056 5010:9057 5010:9058 5010:9059 5011:9054 5011:9055 5011:9056 5011:9057 5011:9058 5011:9059 5012:9054 5012:9055 5012:9056 5012:9057 5012:9058 5012:9059 3001:9060 3001:9061 3001:9062 3001:9063 3001:9064 3001:9065 3002:9060 3002:9061 3002:9062 3002:9063 3002:9064 3002:9065 3003:9060 3003:9061 3003:9062 3003:9063 3003:9064 3003:9065 3004:9060 3004:9061 3004:9062 3004:9063 3004:9064 3004:9065 3005:9060 3005:9061 3005:9062 3005:9063 3005:9064 3005:9065 3006:9060 3006:9061 3006:9062 3006:9063 3006:9064 3006:9065 3007:9060 3007:9061 3007:9062 3007:9063 3007:9064 3007:9065 3008:9060 3008:9061 3008:9062 3008:9063 3008:9064 3008:9065 3009:9060 3009:9061 3009:9062 3009:9063 3009:9064 3009:9065 3010:9060 3010:9061 3010:9062 3010:9063 3010:9064 3010:9065 3011:9060 3011:9061 3011:9062 3011:9063 3011:9064 3011:9065 3012:9060 3012:9061 3012:9062 3012:9063 3012:9064 3012:9065 3013:9060 3013:9061 3013:9062 3013:9063 3013:9064 3013:9065 3014:9060 3014:9061 3014:9062 3014:9063 3014:9064 3014:9065 4001:9060 4001:9061 4001:9062 4001:9063 4001:9064 4001:9065 4002:9060 4002:9061 4002:9062 4002:9063 4002:9064 4002:9065 4003:9060 4003:9061 4003:9062 4003:9063 4003:9064 4003:9065 4004:9060 4004:9061 4004:9062 4004:9063 4004:9064 4004:9065 4005:9060 4005:9061 4005:9062 4005:9063 4005:9064 4005:9065 4006:9060 4006:9061 4006:9062 4006:9063 4006:9064 4006:9065 4007:9060 4007:9061 4007:9062 4007:9063 4007:9064 4007:9065 4008:9060 4008:9061 4008:9062 4008:9063 4008:9064 4008:9065 4009:9060 4009:9061 4009:9062 4009:9063 4009:9064 4009:9065 4010:9060 4010:9061 4010:9062 4010:9063 4010:9064 4010:9065 4011:9060 4011:9061 4011:9062 4011:9063 4011:9064 4011:9065 4012:9060 4012:9061 4012:9062 4012:9063 4012:9064 4012:9065 5001:9060 5001:9061 5001:9062 5001:9063 5001:9064 5001:9065 5002:9060 5002:9061 5002:9062 5002:9063 5002:9064 5002:9065 5003:9060 5003:9061 5003:9062 5003:9063 5003:9064 5003:9065 5004:9060 5004:9061 5004:9062 5004:9063 5004:9064 5004:9065 5005:9060 5005:9061 5005:9062 5005:9063 5005:9064 5005:9065 5006:9060 5006:9061 5006:9062 5006:9063 5006:9064 5006:9065 5007:9060 5007:9061 5007:9062 5007:9063 5007:9064 5007:9065 5008:9060 5008:9061 5008:9062 5008:9063 5008:9064 5008:9065 5009:9060 5009:9061 5009:9062 5009:9063 5009:9064 5009:9065 5010:9060 5010:9061 5010:9062 5010:9063 5010:9064 5010:9065 5011:9060 5011:9061 5011:9062 5011:9063 5011:9064 5011:9065 5012:9060 5012:9061 5012:9062 5012:9063 5012:9064 5012:9065 3001:9066 3001:9067 3001:9068 3001:9069 3001:9070 3001:9071 3002:9066 3002:9067 3002:9068 3002:9069 3002:9070 3002:9071 3003:9066 3003:9067 3003:9068 3003:9069 3003:9070 3003:9071 3004:9066 3004:9067 3004:9068 3004:9069 3004:9070 3004:9071 3005:9066 3005:9067 3005:9068 3005:9069 3005:9070 3005:9071 3006:9066 3006:9067 3006:9068 3006:9069 3006:9070 3006:9071 3007:9066 3007:9067 3007:9068 3007:9069 3007:9070 3007:9071 3008:9066 3008:9067 3008:9068 3008:9069 3008:9070 3008:9071 3009:9066 3009:9067 3009:9068 3009:9069 3009:9070 3009:9071 3010:9066 3010:9067 3010:9068 3010:9069 3010:9070 3010:9071 3011:9066 3011:9067 3011:9068 3011:9069 3011:9070 3011:9071 3012:9066 3012:9067 3012:9068 3012:9069 3012:9070 3012:9071 3013:9066 3013:9067 3013:9068 3013:9069 3013:9070 3013:9071 3014:9066 3014:9067 3014:9068 3014:9069 3014:9070 3014:9071 4001:9066 4001:9067 4001:9068 4001:9069 4001:9070 4001:9071 4002:9066 4002:9067 4002:9068 4002:9069 4002:9070 4002:9071 4003:9066 4003:9067 4003:9068 4003:9069 4003:9070 4003:9071 4004:9066 4004:9067 4004:9068 4004:9069 4004:9070 4004:9071 4005:9066 4005:9067 4005:9068 4005:9069 4005:9070 4005:9071 4006:9066 4006:9067 4006:9068 4006:9069 4006:9070 4006:9071 4007:9066 4007:9067 4007:9068 4007:9069 4007:9070 4007:9071 4008:9066 4008:9067 4008:9068 4008:9069 4008:9070 4008:9071 4009:9066 4009:9067 4009:9068 4009:9069 4009:9070 4009:9071 4010:9066 4010:9067 4010:9068 4010:9069 4010:9070 4010:9071 4011:9066 4011:9067 4011:9068 4011:9069 4011:9070 4011:9071 4012:9066 4012:9067 4012:9068 4012:9069 4012:9070 4012:9071 5001:9066 5001:9067 5001:9068 5001:9069 5001:9070 5001:9071 5002:9066 5002:9067 5002:9068 5002:9069 5002:9070 5002:9071 5003:9066 5003:9067 5003:9068 5003:9069 5003:9070 5003:9071 5004:9066 5004:9067 5004:9068 5004:9069 5004:9070 5004:9071 5005:9066 5005:9067 5005:9068 5005:9069 5005:9070 5005:9071 5006:9066 5006:9067 5006:9068 5006:9069 5006:9070 5006:9071 5007:9066 5007:9067 5007:9068 5007:9069 5007:9070 5007:9071 5008:9066 5008:9067 5008:9068 5008:9069 5008:9070 5008:9071 5009:9066 5009:9067 5009:9068 5009:9069 5009:9070 5009:9071 5010:9066 5010:9067 5010:9068 5010:9069 5010:9070 5010:9071 5011:9066 5011:9067 5011:9068 5011:9069 5011:9070 5011:9071 5012:9066 5012:9067 5012:9068 5012:9069 5012:9070 5012:9071 3001:9072 3001:9073 3001:9074 3001:9075 3001:9076 3001:9077 3002:9072 3002:9073 3002:9074 3002:9075 3002:9076 3002:9077 3003:9072 3003:9073 3003:9074 3003:9075 3003:9076 3003:9077 3004:9072 3004:9073 3004:9074 3004:9075 3004:9076 3004:9077 3005:9072 3005:9073 3005:9074 3005:9075 3005:9076 3005:9077 3006:9072 3006:9073 3006:9074 3006:9075 3006:9076 3006:9077 3007:9072 3007:9073 3007:9074 3007:9075 3007:9076 3007:9077 3008:9072 3008:9073 3008:9074 3008:9075 3008:9076 3008:9077 3009:9072 3009:9073 3009:9074 3009:9075 3009:9076 3009:9077 3010:9072 3010:9073 3010:9074 3010:9075 3010:9076 3010:9077 3011:9072 3011:9073 3011:9074 3011:9075 3011:9076 3011:9077 3012:9072 3012:9073 3012:9074 3012:9075 3012:9076 3012:9077 3013:9072 3013:9073 3013:9074 3013:9075 3013:9076 3013:9077 3014:9072 3014:9073 3014:9074 3014:9075 3014:9076 3014:9077 4001:9072 4001:9073 4001:9074 4001:9075 4001:9076 4001:9077 4002:9072 4002:9073 4002:9074 4002:9075 4002:9076 4002:9077 4003:9072 4003:9073 4003:9074 4003:9075 4003:9076 4003:9077 4004:9072 4004:9073 4004:9074 4004:9075 4004:9076 4004:9077 4005:9072 4005:9073 4005:9074 4005:9075 4005:9076 4005:9077 4006:9072 4006:9073 4006:9074 4006:9075 4006:9076 4006:9077 4007:9072 4007:9073 4007:9074 4007:9075 4007:9076 4007:9077 4008:9072 4008:9073 4008:9074 4008:9075 4008:9076 4008:9077 4009:9072 4009:9073 4009:9074 4009:9075 4009:9076 4009:9077 4010:9072 4010:9073 4010:9074 4010:9075 4010:9076 4010:9077 4011:9072 4011:9073 4011:9074 4011:9075 4011:9076 4011:9077 4012:9072 4012:9073 4012:9074 4012:9075 4012:9076 4012:9077 5001:9072 5001:9073 5001:9074 5001:9075 5001:9076 5001:9077 5002:9072 5002:9073 5002:9074 5002:9075 5002:9076 5002:9077 5003:9072 5003:9073 5003:9074 5003:9075 5003:9076 5003:9077 5004:9072 5004:9073 5004:9074 5004:9075 5004:9076 5004:9077 5005:9072 5005:9073 5005:9074 5005:9075 5005:9076 5005:9077 5006:9072 5006:9073 5006:9074 5006:9075 5006:9076 5006:9077 5007:9072 5007:9073 5007:9074 5007:9075 5007:9076 5007:9077 5008:9072 5008:9073 5008:9074 5008:9075 5008:9076 5008:9077 5009:9072 5009:9073 5009:9074 5009:9075 5009:9076 5009:9077 5010:9072 5010:9073 5010:9074 5010:9075 5010:9076 5010:9077 5011:9072 5011:9073 5011:9074 5011:9075 5011:9076 5011:9077 5012:9072 5012:9073 5012:9074 5012:9075 5012:9076 5012:9077 3001:9078 3001:9079 3001:9080 3001:9081 3001:9082 3001:9083 3002:9078 3002:9079 3002:9080 3002:9081 3002:9082 3002:9083 3003:9078 3003:9079 3003:9080 3003:9081 3003:9082 3003:9083 3004:9078 3004:9079 3004:9080 3004:9081 3004:9082 3004:9083 3005:9078 3005:9079 3005:9080 3005:9081 3005:9082 3005:9083 3006:9078 3006:9079 3006:9080 3006:9081 3006:9082 3006:9083 3007:9078 3007:9079 3007:9080 3007:9081 3007:9082 3007:9083 3008:9078 3008:9079 3008:9080 3008:9081 3008:9082 3008:9083 3009:9078 3009:9079 3009:9080 3009:9081 3009:9082 3009:9083 3010:9078 3010:9079 3010:9080 3010:9081 3010:9082 3010:9083 3011:9078 3011:9079 3011:9080 3011:9081 3011:9082 3011:9083 3012:9078 3012:9079 3012:9080 3012:9081 3012:9082 3012:9083 3013:9078 3013:9079 3013:9080 3013:9081 3013:9082 3013:9083 3014:9078 3014:9079 3014:9080 3014:9081 3014:9082 3014:9083 4001:9078 4001:9079 4001:9080 4001:9081 4001:9082 4001:9083 4002:9078 4002:9079 4002:9080 4002:9081 4002:9082 4002:9083 4003:9078 4003:9079 4003:9080 4003:9081 4003:9082 4003:9083 4004:9078 4004:9079 4004:9080 4004:9081 4004:9082 4004:9083 4005:9078 4005:9079 4005:9080 4005:9081 4005:9082 4005:9083 4006:9078 4006:9079 4006:9080 4006:9081 4006:9082 4006:9083 4007:9078 4007:9079 4007:9080 4007:9081 4007:9082 4007:9083 4008:9078 4008:9079 4008:9080 4008:9081 4008:9082 4008:9083 4009:9078 4009:9079 4009:9080 4009:9081 4009:9082 4009:9083 4010:9078 4010:9079 4010:9080 4010:9081 4010:9082 4010:9083 4011:9078 4011:9079 4011:9080 4011:9081 4011:9082 4011:9083 4012:9078 4012:9079 4012:9080 4012:9081 4012:9082 4012:9083 5001:9078 5001:9079 5001:9080 5001:9081 5001:9082 5001:9083 5002:9078 5002:9079 5002:9080 5002:9081 5002:9082 5002:9083 5003:9078 5003:9079 5003:9080 5003:9081 5003:9082 5003:9083 5004:9078 5004:9079 5004:9080 5004:9081 5004:9082 5004:9083 5005:9078 5005:9079 5005:9080 5005:9081 5005:9082 5005:9083 5006:9078 5006:9079 5006:9080 5006:9081 5006:9082 5006:9083 5007:9078 5007:9079 5007:9080 5007:9081 5007:9082 5007:9083 5008:9078 5008:9079 5008:9080 5008:9081 5008:9082 5008:9083 5009:9078 5009:9079 5009:9080 5009:9081 5009:9082 5009:9083 5010:9078 5010:9079 5010:9080 5010:9081 5010:9082 5010:9083 5011:9078 5011:9079 5011:9080 5011:9081 5011:9082 5011:9083 5012:9078 5012:9079 5012:9080 5012:9081 5012:9082 5012:9083 3001:9084 3001:9085 3001:9086 3001:9087 3001:9088 3001:9089 3002:9084 3002:9085 3002:9086 3002:9087 3002:9088 3002:9089 3003:9084 3003:9085 3003:9086 3003:9087 3003:9088 3003:9089 3004:9084 3004:9085 3004:9086 3004:9087 3004:9088 3004:9089 3005:9084 3005:9085 3005:9086 3005:9087 3005:9088 3005:9089 3006:9084 3006:9085 3006:9086 3006:9087 3006:9088 3006:9089 3007:9084 3007:9085 3007:9086 3007:9087 3007:9088 3007:9089 3008:9084 3008:9085 3008:9086 3008:9087 3008:9088 3008:9089 3009:9084 3009:9085 3009:9086 3009:9087 3009:9088 3009:9089 3010:9084 3010:9085 3010:9086 3010:9087 3010:9088 3010:9089 3011:9084 3011:9085 3011:9086 3011:9087 3011:9088 3011:9089 3012:9084 3012:9085 3012:9086 3012:9087 3012:9088 3012:9089 3013:9084 3013:9085 3013:9086 3013:9087 3013:9088 3013:9089 3014:9084 3014:9085 3014:9086 3014:9087 3014:9088 3014:9089 4001:9084 4001:9085 4001:9086 4001:9087 4001:9088 4001:9089 4002:9084 4002:9085 4002:9086 4002:9087 4002:9088 4002:9089 4003:9084 4003:9085 4003:9086 4003:9087 4003:9088 4003:9089 4004:9084 4004:9085 4004:9086 4004:9087 4004:9088 4004:9089 4005:9084 4005:9085 4005:9086 4005:9087 4005:9088 4005:9089 4006:9084 4006:9085 4006:9086 4006:9087 4006:9088 4006:9089 4007:9084 4007:9085 4007:9086 4007:9087 4007:9088 4007:9089 4008:9084 4008:9085 4008:9086 4008:9087 4008:9088 4008:9089 4009:9084 4009:9085 4009:9086 4009:9087 4009:9088 4009:9089 4010:9084 4010:9085 4010:9086 4010:9087 4010:9088 4010:9089 4011:9084 4011:9085 4011:9086 4011:9087 4011:9088 4011:9089 4012:9084 4012:9085 4012:9086 4012:9087 4012:9088 4012:9089 5001:9084 5001:9085 5001:9086 5001:9087 5001:9088 5001:9089 5002:9084 5002:9085 5002:9086 5002:9087 5002:9088 5002:9089 5003:9084 5003:9085 5003:9086 5003:9087 5003:9088 5003:9089 5004:9084 5004:9085 5004:9086 5004:9087 5004:9088 5004:9089 5005:9084 5005:9085 5005:9086 5005:9087 5005:9088 5005:9089 5006:9084 5006:9085 5006:9086 5006:9087 5006:9088 5006:9089 5007:9084 5007:9085 5007:9086 5007:9087 5007:9088 5007:9089 5008:9084 5008:9085 5008:9086 5008:9087 5008:9088 5008:9089 5009:9084 5009:9085 5009:9086 5009:9087 5009:9088 5009:9089 5010:9084 5010:9085 5010:9086 5010:9087 5010:9088 5010:9089 5011:9084 5011:9085 5011:9086 5011:9087 5011:9088 5011:9089 5012:9084 5012:9085 5012:9086 5012:9087 5012:9088 5012:9089 3001:9090 3001:9091 3001:9092 3001:9093 3001:9094 3001:9095 3002:9090 3002:9091 3002:9092 3002:9093 3002:9094 3002:9095 3003:9090 3003:9091 3003:9092 3003:9093 3003:9094 3003:9095 3004:9090 3004:9091 3004:9092 3004:9093 3004:9094 3004:9095 3005:9090 3005:9091 3005:9092 3005:9093 3005:9094 3005:9095 3006:9090 3006:9091 3006:9092 3006:9093 3006:9094 3006:9095 3007:9090 3007:9091 3007:9092 3007:9093 3007:9094 3007:9095 3008:9090 3008:9091 3008:9092 3008:9093 3008:9094 3008:9095 3009:9090 3009:9091 3009:9092 3009:9093 3009:9094 3009:9095 3010:9090 3010:9091 3010:9092 3010:9093 3010:9094 3010:9095 3011:9090 3011:9091 3011:9092 3011:9093 3011:9094 3011:9095 3012:9090 3012:9091 3012:9092 3012:9093 3012:9094 3012:9095 3013:9090 3013:9091 3013:9092 3013:9093 3013:9094 3013:9095 3014:9090 3014:9091 3014:9092 3014:9093 3014:9094 3014:9095 4001:9090 4001:9091 4001:9092 4001:9093 4001:9094 4001:9095 4002:9090 4002:9091 4002:9092 4002:9093 4002:9094 4002:9095 4003:9090 4003:9091 4003:9092 4003:9093 4003:9094 4003:9095 4004:9090 4004:9091 4004:9092 4004:9093 4004:9094 4004:9095 4005:9090 4005:9091 4005:9092 4005:9093 4005:9094 4005:9095 4006:9090 4006:9091 4006:9092 4006:9093 4006:9094 4006:9095 4007:9090 4007:9091 4007:9092 4007:9093 4007:9094 4007:9095 4008:9090 4008:9091 4008:9092 4008:9093 4008:9094 4008:9095 4009:9090 4009:9091 4009:9092 4009:9093 4009:9094 4009:9095 4010:9090 4010:9091 4010:9092 4010:9093 4010:9094 4010:9095 4011:9090 4011:9091 4011:9092 4011:9093 4011:9094 4011:9095 4012:9090 4012:9091 4012:9092 4012:9093 4012:9094 4012:9095 5001:9090 5001:9091 5001:9092 5001:9093 5001:9094 5001:9095 5002:9090 5002:9091 5002:9092 5002:9093 5002:9094 5002:9095 5003:9090 5003:9091 5003:9092 5003:9093 5003:9094 5003:9095 5004:9090 5004:9091 5004:9092 5004:9093 5004:9094 5004:9095 5005:9090 5005:9091 5005:9092 5005:9093 5005:9094 5005:9095 5006:9090 5006:9091 5006:9092 5006:9093 5006:9094 5006:9095 5007:9090 5007:9091 5007:9092 5007:9093 5007:9094 5007:9095 5008:9090 5008:9091 5008:9092 5008:9093 5008:9094 5008:9095 5009:9090 5009:9091 5009:9092 5009:9093 5009:9094 5009:9095 5010:9090 5010:9091 5010:9092 5010:9093 5010:9094 5010:9095 5011:9090 5011:9091 5011:9092 5011:9093 5011:9094 5011:9095 5012:9090 5012:9091 5012:9092 5012:9093 5012:9094 5012:9095 3001:9096 3001:9097 3001:9098 3001:9099 3001:9100 3001:9101 3002:9096 3002:9097 3002:9098 3002:9099 3002:9100 3002:9101 3003:9096 3003:9097 3003:9098 3003:9099 3003:9100 3003:9101 3004:9096 3004:9097 3004:9098 3004:9099 3004:9100 3004:9101 3005:9096 3005:9097 3005:9098 3005:9099 3005:9100 3005:9101 3006:9096 3006:9097 3006:9098 3006:9099 3006:9100 3006:9101 3007:9096 3007:9097 3007:9098 3007:9099 3007:9100 3007:9101 3008:9096 3008:9097 3008:9098 3008:9099 3008:9100 3008:9101 3009:9096 3009:9097 3009:9098 3009:9099 3009:9100 3009:9101 3010:9096 3010:9097 3010:9098 3010:9099 3010:9100 3010:9101 3011:9096 3011:9097 3011:9098 3011:9099 3011:9100 3011:9101 3012:9096 3012:9097 3012:9098 3012:9099 3012:9100 3012:9101 3013:9096 3013:9097 3013:9098 3013:9099 3013:9100 3013:9101 3014:9096 3014:9097 3014:9098 3014:9099 3014:9100 3014:9101 4001:9096 4001:9097 4001:9098 4001:9099 4001:9100 4001:9101 4002:9096 4002:9097 4002:9098 4002:9099 4002:9100 4002:9101 4003:9096 4003:9097 4003:9098 4003:9099 4003:9100 4003:9101 4004:9096 4004:9097 4004:9098 4004:9099 4004:9100 4004:9101 4005:9096 4005:9097 4005:9098 4005:9099 4005:9100 4005:9101 4006:9096 4006:9097 4006:9098 4006:9099 4006:9100 4006:9101 4007:9096 4007:9097 4007:9098 4007:9099 4007:9100 4007:9101 4008:9096 4008:9097 4008:9098 4008:9099 4008:9100 4008:9101 4009:9096 4009:9097 4009:9098 4009:9099 4009:9100 4009:9101 4010:9096 4010:9097 4010:9098 4010:9099 4010:9100 4010:9101 4011:9096 4011:9097 4011:9098 4011:9099 4011:9100 4011:9101 4012:9096 4012:9097 4012:9098 4012:9099 4012:9100 4012:9101 5001:9096 5001:9097 5001:9098 5001:9099 5001:9100 5001:9101 5002:9096 5002:9097 5002:9098 5002:9099 5002:9100 5002:9101 5003:9096 5003:9097 5003:9098 5003:9099 5003:9100 5003:9101 5004:9096 5004:9097 5004:9098 5004:9099 5004:9100 5004:9101 5005:9096 5005:9097 5005:9098 5005:9099 5005:9100 5005:9101 5006:9096 5006:9097 5006:9098 5006:9099 5006:9100 5006:9101 5007:9096 5007:9097 5007:9098 5007:9099 5007:9100 5007:9101 5008:9096 5008:9097 5008:9098 5008:9099 5008:9100 5008:9101 5009:9096 5009:9097 5009:9098 5009:9099 5009:9100 5009:9101 5010:9096 5010:9097 5010:9098 5010:9099 5010:9100 5010:9101 5011:9096 5011:9097 5011:9098 5011:9099 5011:9100 5011:9101 5012:9096 5012:9097 5012:9098 5012:9099 5012:9100 5012:9101 3001:9102 3001:9103 3001:9104 3001:9105 — — 3002:9102 3002:9103 3002:9104 3002:9105 3003:9102 3003:9103 3003:9104 3003:9105 3004:9102 3004:9103 3004:9104 3004:9105 3005:9102 3005:9103 3005:9104 3005:9105 3006:9102 3006:9103 3006:9104 3006:9105 3007:9102 3007:9103 3007:9104 3007:9105 3008:9102 3008:9103 3008:9104 3008:9105 3009:9102 3009:9103 3009:9104 3009:9105 3010:9102 3010:9103 3010:9104 3010:9105 3011:9102 3011:9103 3011:9104 3011:9105 3012:9102 3012:9103 3012:9104 3012:9105 3013:9102 3013:9103 3013:9104 3013:9105 3014:9102 3014:9103 3014:9104 3014:9105 4001:9102 4001:9103 4001:9104 4001:9105 4002:9102 4002:9103 4002:9104 4002:9105 4003:9102 4003:9103 4003:9104 4003:9105 4004:9102 4004:9103 4004:9104 4004:9105 4005:9102 4005:9103 4005:9104 4005:9105 4006:9102 4006:9103 4006:9104 4006:9105 4007:9102 4007:9103 4007:9104 4007:9105 4008:9102 4008:9103 4008:9104 4008:9105 4009:9102 4009:9103 4009:9104 4009:9105 4010:9102 4010:9103 4010:9104 4010:9105 4011:9102 4011:9103 4011:9104 4011:9105 4012:9102 4012:9103 4012:9104 4012:9105 5001:9102 5001:9103 5001:9104 5001:9105 5002:9102 5002:9103 5002:9104 5002:9105 5003:9102 5003:9103 5003:9104 5003:9105 5004:9102 5004:9103 5004:9104 5004:9105 5005:9102 5005:9103 5005:9104 5005:9105 5006:9102 5006:9103 5006:9104 5006:9105 5007:9102 5007:9103 5007:9104 5007:9105 5008:9102 5008:9103 5008:9104 5008:9105 5009:9102 5009:9103 5009:9104 5009:9105 5010:9102 5010:9103 5010:9104 5010:9105 5011:9102 5011:9103 5011:9104 5011:9105 5012:9102 5012:9103 5012:9104 5012:9105

TABLE C Example combinations of a compound X with a compound Y. X:Y X:Y X:Y X:Y X:Y X:Y 9000:7000 9001:7000 9002:7000 9003:7000 9004:7000 9005:7000 9000:7001 9001:7001 9002:7001 9003:7001 9004:7001 9005:7001 9000:7002 9001:7002 9002:7002 9003:7002 9004:7002 9005:7002 9000:7003 9001:7003 9002:7003 9003:7003 9004:7003 9005:7003 9000:7004 9001:7004 9002:7004 9003:7004 9004:7004 9005:7004 9000:7005 9001:7005 9002:7005 9003:7005 9004:7005 9005:7005 9000:7006 9001:7006 9002:7006 9003:7006 9004:7006 9005:7006 9000:7007 9001:7007 9002:7007 9003:7007 9004:7007 9005:7007 9000:7008 9001:7008 9002:7008 9003:7008 9004:7008 9005:7008 9000:7009 9001:7009 9002:7009 9003:7009 9004:7009 9005:7009 9000:7010 9001:7010 9002:7010 9003:7010 9004:7010 9005:7010 9000:7011 9001:7011 9002:7011 9003:7011 9004:7011 9005:7011 9000:7012 9001:7012 9002:7012 9003:7012 9004:7012 9005:7012 9000:7013 9001:7013 9002:7013 9003:7013 9004:7013 9005:7013 9000:7014 9001:7014 9002:7014 9003:7014 9004:7014 9005:7014 9000:7015 9001:7015 9002:7015 9003:7015 9004:7015 9005:7015 9000:7016 9001:7016 9002:7016 9003:7016 9004:7016 9005:7016 9000:7017 9001:7017 9002:7017 9003:7017 9004:7017 9005:7017 9000:7018 9001:7018 9002:7018 9003:7018 9004:7018 9005:7018 9000:7019 9001:7019 9002:7019 9003:7019 9004:7019 9005:7019 9000:7020 9001:7020 9002:7020 9003:7020 9004:7020 9005:7020 9000:7021 9001:7021 9002:7021 9003:7021 9004:7021 9005:7021 9000:7022 9001:7022 9002:7022 9003:7022 9004:7022 9005:7022 9000:7023 9001:7023 9002:7023 9003:7023 9004:7023 9005:7023 9000:7024 9001:7024 9002:7024 9003:7024 9004:7024 9005:7024 9000:7025 9001:7025 9002:7025 9003:7025 9004:7025 9005:7025 9000:7026 9001:7026 9002:7026 9003:7026 9004:7026 9005:7026 9000:7027 9001:7027 9002:7027 9003:7027 9004:7027 9005:7027 9006:7000 9007:7000 9008:7000 9009:7000 9010:7000 9011:7000 9006:7001 9007:7001 9008:7001 9009:7001 9010:7001 9011:7001 9006:7002 9007:7002 9008:7002 9009:7002 9010:7002 9011:7002 9006:7003 9007:7003 9008:7003 9009:7003 9010:7003 9011:7003 9006:7004 9007:7004 9008:7004 9009:7004 9010:7004 9011:7004 9006:7005 9007:7005 9008:7005 9009:7005 9010:7005 9011:7005 9006:7006 9007:7006 9008:7006 9009:7006 9010:7006 9011:7006 9006:7007 9007:7007 9008:7007 9009:7007 9010:7007 9011:7007 9006:7008 9007:7008 9008:7008 9009:7008 9010:7008 9011:7008 9006:7009 9007:7009 9008:7009 9009:7009 9010:7009 9011:7009 9006:7010 9007:7010 9008:7010 9009:7010 9010:7010 9011:7010 9006:7011 9007:7011 9008:7011 9009:7011 9010:7011 9011:7011 9006:7012 9007:7012 9008:7012 9009:7012 9010:7012 9011:7012 9006:7013 9007:7013 9008:7013 9009:7013 9010:7013 9011:7013 9006:7014 9007:7014 9008:7014 9009:7014 9010:7014 9011:7014 9006:7015 9007:7015 9008:7015 9009:7015 9010:7015 9011:7015 9006:7016 9007:7016 9008:7016 9009:7016 9010:7016 9011:7016 9006:7017 9007:7017 9008:7017 9009:7017 9010:7017 9011:7017 9006:7018 9007:7018 9008:7018 9009:7018 9010:7018 9011:7018 9006:7019 9007:7019 9008:7019 9009:7019 9010:7019 9011:7019 9006:7020 9007:7020 9008:7020 9009:7020 9010:7020 9011:7020 9006:7021 9007:7021 9008:7021 9009:7021 9010:7021 9011:7021 9006:7022 9007:7022 9008:7022 9009:7022 9010:7022 9011:7022 9006:7023 9007:7023 9008:7023 9009:7023 9010:7023 9011:7023 9006:7024 9007:7024 9008:7024 9009:7024 9010:7024 9011:7024 9006:7025 9007:7025 9008:7025 9009:7025 9010:7025 9011:7025 9006:7026 9007:7026 9008:7026 9009:7026 9010:7026 9011:7026 9006:7027 9007:7027 9008:7027 9009:7027 9010:7027 9011:7027 9012:7000 9013:7000 9014:7000 9015:7000 9016:7000 9017:7000 9012:7001 9013:7001 9014:7001 9015:7001 9016:7001 9017:7001 9012:7002 9013:7002 9014:7002 9015:7002 9016:7002 9017:7002 9012:7003 9013:7003 9014:7003 9015:7003 9016:7003 9017:7003 9012:7004 9013:7004 9014:7004 9015:7004 9016:7004 9017:7004 9012:7005 9013:7005 9014:7005 9015:7005 9016:7005 9017:7005 9012:7006 9013:7006 9014:7006 9015:7006 9016:7006 9017:7006 9012:7007 9013:7007 9014:7007 9015:7007 9016:7007 9017:7007 9012:7008 9013:7008 9014:7008 9015:7008 9016:7008 9017:7008 9012:7009 9013:7009 9014:7009 9015:7009 9016:7009 9017:7009 9012:7010 9013:7010 9014:7010 9015:7010 9016:7010 9017:7010 9012:7011 9013:7011 9014:7011 9015:7011 9016:7011 9017:7011 9012:7012 9013:7012 9014:7012 9015:7012 9016:7012 9017:7012 9012:7013 9013:7013 9014:7013 9015:7013 9016:7013 9017:7013 9012:7014 9013:7014 9014:7014 9015:7014 9016:7014 9017:7014 9012:7015 9013:7015 9014:7015 9015:7015 9016:7015 9017:7015 9012:7016 9013:7016 9014:7016 9015:7016 9016:7016 9017:7016 9012:7017 9013:7017 9014:7017 9015:7017 9016:7017 9017:7017 9012:7018 9013:7018 9014:7018 9015:7018 9016:7018 9017:7018 9012:7019 9013:7019 9014:7019 9015:7019 9016:7019 9017:7019 9012:7020 9013:7020 9014:7020 9015:7020 9016:7020 9017:7020 9012:7021 9013:7021 9014:7021 9015:7021 9016:7021 9017:7021 9012:7022 9013:7022 9014:7022 9015:7022 9016:7022 9017:7022 9012:7023 9013:7023 9014:7023 9015:7023 9016:7023 9017:7023 9012:7024 9013:7024 9014:7024 9015:7024 9016:7024 9017:7024 9012:7025 9013:7025 9014:7025 9015:7025 9016:7025 9017:7025 9012:7026 9013:7026 9014:7026 9015:7026 9016:7026 9017:7026 9012:7027 9013:7027 9014:7027 9015:7027 9016:7027 9017:7027 9018:7000 9019:7000 9020:7000 9021:7000 9022:7000 9023:7000 9018:7001 9019:7001 9020:7001 9021:7001 9022:7001 9023:7001 9018:7002 9019:7002 9020:7002 9021:7002 9022:7002 9023:7002 9018:7003 9019:7003 9020:7003 9021:7003 9022:7003 9023:7003 9018:7004 9019:7004 9020:7004 9021:7004 9022:7004 9023:7004 9018:7005 9019:7005 9020:7005 9021:7005 9022:7005 9023:7005 9018:7006 9019:7006 9020:7006 9021:7006 9022:7006 9023:7006 9018:7007 9019:7007 9020:7007 9021:7007 9022:7007 9023:7007 9018:7008 9019:7008 9020:7008 9021:7008 9022:7008 9023:7008 9018:7009 9019:7009 9020:7009 9021:7009 9022:7009 9023:7009 9018:7010 9019:7010 9020:7010 9021:7010 9022:7010 9023:7010 9018:7011 9019:7011 9020:7011 9021:7011 9022:7011 9023:7011 9018:7012 9019:7012 9020:7012 9021:7012 9022:7012 9023:7012 9018:7013 9019:7013 9020:7013 9021:7013 9022:7013 9023:7013 9018:7014 9019:7014 9020:7014 9021:7014 9022:7014 9023:7014 9018:7015 9019:7015 9020:7015 9021:7015 9022:7015 9023:7015 9018:7016 9019:7016 9020:7016 9021:7016 9022:7016 9023:7016 9018:7017 9019:7017 9020:7017 9021:7017 9022:7017 9023:7017 9018:7018 9019:7018 9020:7018 9021:7018 9022:7018 9023:7018 9018:7019 9019:7019 9020:7019 9021:7019 9022:7019 9023:7019 9018:7020 9019:7020 9020:7020 9021:7020 9022:7020 9023:7020 9018:7021 9019:7021 9020:7021 9021:7021 9022:7021 9023:7021 9018:7022 9019:7022 9020:7022 9021:7022 9022:7022 9023:7022 9018:7023 9019:7023 9020:7023 9021:7023 9022:7023 9023:7023 9018:7024 9019:7024 9020:7024 9021:7024 9022:7024 9023:7024 9018:7025 9019:7025 9020:7025 9021:7025 9022:7025 9023:7025 9018:7026 9019:7026 9020:7026 9021:7026 9022:7026 9023:7026 9018:7027 9019:7027 9020:7027 9021:7027 9022:7027 9023:7027 9024:7000 9025:7000 9026:7000 9027:7000 9028:7000 9029:7000 9024:7001 9025:7001 9026:7001 9027:7001 9028:7001 9029:7001 9024:7002 9025:7002 9026:7002 9027:7002 9028:7002 9029:7002 9024:7003 9025:7003 9026:7003 9027:7003 9028:7003 9029:7003 9024:7004 9025:7004 9026:7004 9027:7004 9028:7004 9029:7004 9024:7005 9025:7005 9026:7005 9027:7005 9028:7005 9029:7005 9024:7006 9025:7006 9026:7006 9027:7006 9028:7006 9029:7006 9024:7007 9025:7007 9026:7007 9027:7007 9028:7007 9029:7007 9024:7008 9025:7008 9026:7008 9027:7008 9028:7008 9029:7008 9024:7009 9025:7009 9026:7009 9027:7009 9028:7009 9029:7009 9024:7010 9025:7010 9026:7010 9027:7010 9028:7010 9029:7010 9024:7011 9025:7011 9026:7011 9027:7011 9028:7011 9029:7011 9024:7012 9025:7012 9026:7012 9027:7012 9028:7012 9029:7012 9024:7013 9025:7013 9026:7013 9027:7013 9028:7013 9029:7013 9024:7014 9025:7014 9026:7014 9027:7014 9028:7014 9029:7014 9024:7015 9025:7015 9026:7015 9027:7015 9028:7015 9029:7015 9024:7016 9025:7016 9026:7016 9027:7016 9028:7016 9029:7016 9024:7017 9025:7017 9026:7017 9027:7017 9028:7017 9029:7017 9024:7018 9025:7018 9026:7018 9027:7018 9028:7018 9029:7018 9024:7019 9025:7019 9026:7019 9027:7019 9028:7019 9029:7019 9024:7020 9025:7020 9026:7020 9027:7020 9028:7020 9029:7020 9024:7021 9025:7021 9026:7021 9027:7021 9028:7021 9029:7021 9024:7022 9025:7022 9026:7022 9027:7022 9028:7022 9029:7022 9024:7023 9025:7023 9026:7023 9027:7023 9028:7023 9029:7023 9024:7024 9025:7024 9026:7024 9027:7024 9028:7024 9029:7024 9024:7025 9025:7025 9026:7025 9027:7025 9028:7025 9029:7025 9024:7026 9025:7026 9026:7026 9027:7026 9028:7026 9029:7026 9024:7027 9025:7027 9026:7027 9027:7027 9028:7027 9029:7027 9030:7000 9031:7000 9032:7000 9033:7000 9034:7000 9035:7000 9030:7001 9031:7001 9032:7001 9033:7001 9034:7001 9035:7001 9030:7002 9031:7002 9032:7002 9033:7002 9034:7002 9035:7002 9030:7003 9031:7003 9032:7003 9033:7003 9034:7003 9035:7003 9030:7004 9031:7004 9032:7004 9033:7004 9034:7004 9035:7004 9030:7005 9031:7005 9032:7005 9033:7005 9034:7005 9035:7005 9030:7006 9031:7006 9032:7006 9033:7006 9034:7006 9035:7006 9030:7007 9031:7007 9032:7007 9033:7007 9034:7007 9035:7007 9030:7008 9031:7008 9032:7008 9033:7008 9034:7008 9035:7008 9030:7009 9031:7009 9032:7009 9033:7009 9034:7009 9035:7009 9030:7010 9031:7010 9032:7010 9033:7010 9034:7010 9035:7010 9030:7011 9031:7011 9032:7011 9033:7011 9034:7011 9035:7011 9030:7012 9031:7012 9032:7012 9033:7012 9034:7012 9035:7012 9030:7013 9031:7013 9032:7013 9033:7013 9034:7013 9035:7013 9030:7014 9031:7014 9032:7014 9033:7014 9034:7014 9035:7014 9030:7015 9031:7015 9032:7015 9033:7015 9034:7015 9035:7015 9030:7016 9031:7016 9032:7016 9033:7016 9034:7016 9035:7016 9030:7017 9031:7017 9032:7017 9033:7017 9034:7017 9035:7017 9030:7018 9031:7018 9032:7018 9033:7018 9034:7018 9035:7018 9030:7019 9031:7019 9032:7019 9033:7019 9034:7019 9035:7019 9030:7020 9031:7020 9032:7020 9033:7020 9034:7020 9035:7020 9030:7021 9031:7021 9032:7021 9033:7021 9034:7021 9035:7021 9030:7022 9031:7022 9032:7022 9033:7022 9034:7022 9035:7022 9030:7023 9031:7023 9032:7023 9033:7023 9034:7023 9035:7023 9030:7024 9031:7024 9032:7024 9033:7024 9034:7024 9035:7024 9030:7025 9031:7025 9032:7025 9033:7025 9034:7025 9035:7025 9030:7026 9031:7026 9032:7026 9033:7026 9034:7026 9035:7026 9030:7027 9031:7027 9032:7027 9033:7027 9034:7027 9035:7027 9036:7000 9037:7000 9038:7000 9039:7000 9040:7000 9041:7000 9036:7001 9037:7001 9038:7001 9039:7001 9040:7001 9041:7001 9036:7002 9037:7002 9038:7002 9039:7002 9040:7002 9041:7002 9036:7003 9037:7003 9038:7003 9039:7003 9040:7003 9041:7003 9036:7004 9037:7004 9038:7004 9039:7004 9040:7004 9041:7004 9036:7005 9037:7005 9038:7005 9039:7005 9040:7005 9041:7005 9036:7006 9037:7006 9038:7006 9039:7006 9040:7006 9041:7006 9036:7007 9037:7007 9038:7007 9039:7007 9040:7007 9041:7007 9036:7008 9037:7008 9038:7008 9039:7008 9040:7008 9041:7008 9036:7009 9037:7009 9038:7009 9039:7009 9040:7009 9041:7009 9036:7010 9037:7010 9038:7010 9039:7010 9040:7010 9041:7010 9036:7011 9037:7011 9038:7011 9039:7011 9040:7011 9041:7011 9036:7012 9037:7012 9038:7012 9039:7012 9040:7012 9041:7012 9036:7013 9037:7013 9038:7013 9039:7013 9040:7013 9041:7013 9036:7014 9037:7014 9038:7014 9039:7014 9040:7014 9041:7014 9036:7015 9037:7015 9038:7015 9039:7015 9040:7015 9041:7015 9036:7016 9037:7016 9038:7016 9039:7016 9040:7016 9041:7016 9036:7017 9037:7017 9038:7017 9039:7017 9040:7017 9041:7017 9036:7018 9037:7018 9038:7018 9039:7018 9040:7018 9041:7018 9036:7019 9037:7019 9038:7019 9039:7019 9040:7019 9041:7019 9036:7020 9037:7020 9038:7020 9039:7020 9040:7020 9041:7020 9036:7021 9037:7021 9038:7021 9039:7021 9040:7021 9041:7021 9036:7022 9037:7022 9038:7022 9039:7022 9040:7022 9041:7022 9036:7023 9037:7023 9038:7023 9039:7023 9040:7023 9041:7023 9036:7024 9037:7024 9038:7024 9039:7024 9040:7024 9041:7024 9036:7025 9037:7025 9038:7025 9039:7025 9040:7025 9041:7025 9036:7026 9037:7026 9038:7026 9039:7026 9040:7026 9041:7026 9036:7027 9037:7027 9038:7027 9039:7027 9040:7027 9041:7027 9042:7000 9043:7000 9044:7000 9045:7000 9046:7000 9047:7000 9042:7001 9043:7001 9044:7001 9045:7001 9046:7001 9047:7001 9042:7002 9043:7002 9044:7002 9045:7002 9046:7002 9047:7002 9042:7003 9043:7003 9044:7003 9045:7003 9046:7003 9047:7003 9042:7004 9043:7004 9044:7004 9045:7004 9046:7004 9047:7004 9042:7005 9043:7005 9044:7005 9045:7005 9046:7005 9047:7005 9042:7006 9043:7006 9044:7006 9045:7006 9046:7006 9047:7006 9042:7007 9043:7007 9044:7007 9045:7007 9046:7007 9047:7007 9042:7008 9043:7008 9044:7008 9045:7008 9046:7008 9047:7008 9042:7009 9043:7009 9044:7009 9045:7009 9046:7009 9047:7009 9042:7010 9043:7010 9044:7010 9045:7010 9046:7010 9047:7010 9042:7011 9043:7011 9044:7011 9045:7011 9046:7011 9047:7011 9042:7012 9043:7012 9044:7012 9045:7012 9046:7012 9047:7012 9042:7013 9043:7013 9044:7013 9045:7013 9046:7013 9047:7013 9042:7014 9043:7014 9044:7014 9045:7014 9046:7014 9047:7014 9042:7015 9043:7015 9044:7015 9045:7015 9046:7015 9047:7015 9042:7016 9043:7016 9044:7016 9045:7016 9046:7016 9047:7016 9042:7017 9043:7017 9044:7017 9045:7017 9046:7017 9047:7017 9042:7018 9043:7018 9044:7018 9045:7018 9046:7018 9047:7018 9042:7019 9043:7019 9044:7019 9045:7019 9046:7019 9047:7019 9042:7020 9043:7020 9044:7020 9045:7020 9046:7020 9047:7020 9042:7021 9043:7021 9044:7021 9045:7021 9046:7021 9047:7021 9042:7022 9043:7022 9044:7022 9045:7022 9046:7022 9047:7022 9042:7023 9043:7023 9044:7023 9045:7023 9046:7023 9047:7023 9042:7024 9043:7024 9044:7024 9045:7024 9046:7024 9047:7024 9042:7025 9043:7025 9044:7025 9045:7025 9046:7025 9047:7025 9042:7026 9043:7026 9044:7026 9045:7026 9046:7026 9047:7026 9042:7027 9043:7027 9044:7027 9045:7027 9046:7027 9047:7027 9048:7000 9049:7000 9050:7000 9051:7000 9052:7000 9053:7000 9048:7001 9049:7001 9050:7001 9051:7001 9052:7001 9053:7001 9048:7002 9049:7002 9050:7002 9051:7002 9052:7002 9053:7002 9048:7003 9049:7003 9050:7003 9051:7003 9052:7003 9053:7003 9048:7004 9049:7004 9050:7004 9051:7004 9052:7004 9053:7004 9048:7005 9049:7005 9050:7005 9051:7005 9052:7005 9053:7005 9048:7006 9049:7006 9050:7006 9051:7006 9052:7006 9053:7006 9048:7007 9049:7007 9050:7007 9051:7007 9052:7007 9053:7007 9048:7008 9049:7008 9050:7008 9051:7008 9052:7008 9053:7008 9048:7009 9049:7009 9050:7009 9051:7009 9052:7009 9053:7009 9048:7010 9049:7010 9050:7010 9051:7010 9052:7010 9053:7010 9048:7011 9049:7011 9050:7011 9051:7011 9052:7011 9053:7011 9048:7012 9049:7012 9050:7012 9051:7012 9052:7012 9053:7012 9048:7013 9049:7013 9050:7013 9051:7013 9052:7013 9053:7013 9048:7014 9049:7014 9050:7014 9051:7014 9052:7014 9053:7014 9048:7015 9049:7015 9050:7015 9051:7015 9052:7015 9053:7015 9048:7016 9049:7016 9050:7016 9051:7016 9052:7016 9053:7016 9048:7017 9049:7017 9050:7017 9051:7017 9052:7017 9053:7017 9048:7018 9049:7018 9050:7018 9051:7018 9052:7018 9053:7018 9048:7019 9049:7019 9050:7019 9051:7019 9052:7019 9053:7019 9048:7020 9049:7020 9050:7020 9051:7020 9052:7020 9053:7020 9048:7021 9049:7021 9050:7021 9051:7021 9052:7021 9053:7021 9048:7022 9049:7022 9050:7022 9051:7022 9052:7022 9053:7022 9048:7023 9049:7023 9050:7023 9051:7023 9052:7023 9053:7023 9048:7024 9049:7024 9050:7024 9051:7024 9052:7024 9053:7024 9048:7025 9049:7025 9050:7025 9051:7025 9052:7025 9053:7025 9048:7026 9049:7026 9050:7026 9051:7026 9052:7026 9053:7026 9048:7027 9049:7027 9050:7027 9051:7027 9052:7027 9053:7027 9054:7000 9055:7000 9056:7000 9057:7000 9058:7000 9059:7000 9054:7001 9055:7001 9056:7001 9057:7001 9058:7001 9059:7001 9054:7002 9055:7002 9056:7002 9057:7002 9058:7002 9059:7002 9054:7003 9055:7003 9056:7003 9057:7003 9058:7003 9059:7003 9054:7004 9055:7004 9056:7004 9057:7004 9058:7004 9059:7004 9054:7005 9055:7005 9056:7005 9057:7005 9058:7005 9059:7005 9054:7006 9055:7006 9056:7006 9057:7006 9058:7006 9059:7006 9054:7007 9055:7007 9056:7007 9057:7007 9058:7007 9059:7007 9054:7008 9055:7008 9056:7008 9057:7008 9058:7008 9059:7008 9054:7009 9055:7009 9056:7009 9057:7009 9058:7009 9059:7009 9054:7010 9055:7010 9056:7010 9057:7010 9058:7010 9059:7010 9054:7011 9055:7011 9056:7011 9057:7011 9058:7011 9059:7011 9054:7012 9055:7012 9056:7012 9057:7012 9058:7012 9059:7012 9054:7013 9055:7013 9056:7013 9057:7013 9058:7013 9059:7013 9054:7014 9055:7014 9056:7014 9057:7014 9058:7014 9059:7014 9054:7015 9055:7015 9056:7015 9057:7015 9058:7015 9059:7015 9054:7016 9055:7016 9056:7016 9057:7016 9058:7016 9059:7016 9054:7017 9055:7017 9056:7017 9057:7017 9058:7017 9059:7017 9054:7018 9055:7018 9056:7018 9057:7018 9058:7018 9059:7018 9054:7019 9055:7019 9056:7019 9057:7019 9058:7019 9059:7019 9054:7020 9055:7020 9056:7020 9057:7020 9058:7020 9059:7020 9054:7021 9055:7021 9056:7021 9057:7021 9058:7021 9059:7021 9054:7022 9055:7022 9056:7022 9057:7022 9058:7022 9059:7022 9054:7023 9055:7023 9056:7023 9057:7023 9058:7023 9059:7023 9054:7024 9055:7024 9056:7024 9057:7024 9058:7024 9059:7024 9054:7025 9055:7025 9056:7025 9057:7025 9058:7025 9059:7025 9054:7026 9055:7026 9056:7026 9057:7026 9058:7026 9059:7026 9054:7027 9055:7027 9056:7027 9057:7027 9058:7027 9059:7027 9060:7000 9061:7000 9062:7000 9063:7000 9064:7000 9065:7000 9060:7001 9061:7001 9062:7001 9063:7001 9064:7001 9065:7001 9060:7002 9061:7002 9062:7002 9063:7002 9064:7002 9065:7002 9060:7003 9061:7003 9062:7003 9063:7003 9064:7003 9065:7003 9060:7004 9061:7004 9062:7004 9063:7004 9064:7004 9065:7004 9060:7005 9061:7005 9062:7005 9063:7005 9064:7005 9065:7005 9060:7006 9061:7006 9062:7006 9063:7006 9064:7006 9065:7006 9060:7007 9061:7007 9062:7007 9063:7007 9064:7007 9065:7007 9060:7008 9061:7008 9062:7008 9063:7008 9064:7008 9065:7008 9060:7009 9061:7009 9062:7009 9063:7009 9064:7009 9065:7009 9060:7010 9061:7010 9062:7010 9063:7010 9064:7010 9065:7010 9060:7011 9061:7011 9062:7011 9063:7011 9064:7011 9065:7011 9060:7012 9061:7012 9062:7012 9063:7012 9064:7012 9065:7012 9060:7013 9061:7013 9062:7013 9063:7013 9064:7013 9065:7013 9060:7014 9061:7014 9062:7014 9063:7014 9064:7014 9065:7014 9060:7015 9061:7015 9062:7015 9063:7015 9064:7015 9065:7015 9060:7016 9061:7016 9062:7016 9063:7016 9064:7016 9065:7016 9060:7017 9061:7017 9062:7017 9063:7017 9064:7017 9065:7017 9060:7018 9061:7018 9062:7018 9063:7018 9064:7018 9065:7018 9060:7019 9061:7019 9062:7019 9063:7019 9064:7019 9065:7019 9060:7020 9061:7020 9062:7020 9063:7020 9064:7020 9065:7020 9060:7021 9061:7021 9062:7021 9063:7021 9064:7021 9065:7021 9060:7022 9061:7022 9062:7022 9063:7022 9064:7022 9065:7022 9060:7023 9061:7023 9062:7023 9063:7023 9064:7023 9065:7023 9060:7024 9061:7024 9062:7024 9063:7024 9064:7024 9065:7024 9060:7025 9061:7025 9062:7025 9063:7025 9064:7025 9065:7025 9060:7026 9061:7026 9062:7026 9063:7026 9064:7026 9065:7026 9060:7027 9061:7027 9062:7027 9063:7027 9064:7027 9065:7027 9066:7000 9067:7000 9068:7000 9069:7000 9070:7000 9071:7000 9066:7001 9067:7001 9068:7001 9069:7001 9070:7001 9071:7001 9066:7002 9067:7002 9068:7002 9069:7002 9070:7002 9071:7002 9066:7003 9067:7003 9068:7003 9069:7003 9070:7003 9071:7003 9066:7004 9067:7004 9068:7004 9069:7004 9070:7004 9071:7004 9066:7005 9067:7005 9068:7005 9069:7005 9070:7005 9071:7005 9066:7006 9067:7006 9068:7006 9069:7006 9070:7006 9071:7006 9066:7007 9067:7007 9068:7007 9069:7007 9070:7007 9071:7007 9066:7008 9067:7008 9068:7008 9069:7008 9070:7008 9071:7008 9066:7009 9067:7009 9068:7009 9069:7009 9070:7009 9071:7009 9066:7010 9067:7010 9068:7010 9069:7010 9070:7010 9071:7010 9066:7011 9067:7011 9068:7011 9069:7011 9070:7011 9071:7011 9066:7012 9067:7012 9068:7012 9069:7012 9070:7012 9071:7012 9066:7013 9067:7013 9068:7013 9069:7013 9070:7013 9071:7013 9066:7014 9067:7014 9068:7014 9069:7014 9070:7014 9071:7014 9066:7015 9067:7015 9068:7015 9069:7015 9070:7015 9071:7015 9066:7016 9067:7016 9068:7016 9069:7016 9070:7016 9071:7016 9066:7017 9067:7017 9068:7017 9069:7017 9070:7017 9071:7017 9066:7018 9067:7018 9068:7018 9069:7018 9070:7018 9071:7018 9066:7019 9067:7019 9068:7019 9069:7019 9070:7019 9071:7019 9066:7020 9067:7020 9068:7020 9069:7020 9070:7020 9071:7020 9066:7021 9067:7021 9068:7021 9069:7021 9070:7021 9071:7021 9066:7022 9067:7022 9068:7022 9069:7022 9070:7022 9071:7022 9066:7023 9067:7023 9068:7023 9069:7023 9070:7023 9071:7023 9066:7024 9067:7024 9068:7024 9069:7024 9070:7024 9071:7024 9066:7025 9067:7025 9068:7025 9069:7025 9070:7025 9071:7025 9066:7026 9067:7026 9068:7026 9069:7026 9070:7026 9071:7026 9066:7027 9067:7027 9068:7027 9069:7027 9070:7027 9071:7027 9072:7000 9073:7000 9074:7000 9075:7000 9076:7000 9077:7000 9072:7001 9073:7001 9074:7001 9075:7001 9076:7001 9077:7001 9072:7002 9073:7002 9074:7002 9075:7002 9076:7002 9077:7002 9072:7003 9073:7003 9074:7003 9075:7003 9076:7003 9077:7003 9072:7004 9073:7004 9074:7004 9075:7004 9076:7004 9077:7004 9072:7005 9073:7005 9074:7005 9075:7005 9076:7005 9077:7005 9072:7006 9073:7006 9074:7006 9075:7006 9076:7006 9077:7006 9072:7007 9073:7007 9074:7007 9075:7007 9076:7007 9077:7007 9072:7008 9073:7008 9074:7008 9075:7008 9076:7008 9077:7008 9072:7009 9073:7009 9074:7009 9075:7009 9076:7009 9077:7009 9072:7010 9073:7010 9074:7010 9075:7010 9076:7010 9077:7010 9072:7011 9073:7011 9074:7011 9075:7011 9076:7011 9077:7011 9072:7012 9073:7012 9074:7012 9075:7012 9076:7012 9077:7012 9072:7013 9073:7013 9074:7013 9075:7013 9076:7013 9077:7013 9072:7014 9073:7014 9074:7014 9075:7014 9076:7014 9077:7014 9072:7015 9073:7015 9074:7015 9075:7015 9076:7015 9077:7015 9072:7016 9073:7016 9074:7016 9075:7016 9076:7016 9077:7016 9072:7017 9073:7017 9074:7017 9075:7017 9076:7017 9077:7017 9072:7018 9073:7018 9074:7018 9075:7018 9076:7018 9077:7018 9072:7019 9073:7019 9074:7019 9075:7019 9076:7019 9077:7019 9072:7020 9073:7020 9074:7020 9075:7020 9076:7020 9077:7020 9072:7021 9073:7021 9074:7021 9075:7021 9076:7021 9077:7021 9072:7022 9073:7022 9074:7022 9075:7022 9076:7022 9077:7022 9072:7023 9073:7023 9074:7023 9075:7023 9076:7023 9077:7023 9072:7024 9073:7024 9074:7024 9075:7024 9076:7024 9077:7024 9072:7025 9073:7025 9074:7025 9075:7025 9076:7025 9077:7025 9072:7026 9073:7026 9074:7026 9075:7026 9076:7026 9077:7026 9072:7027 9073:7027 9074:7027 9075:7027 9076:7027 9077:7027 9078:7000 9079:7000 9080:7000 9081:7000 9082:7000 9083:7000 9078:7001 9079:7001 9080:7001 9081:7001 9082:7001 9083:7001 9078:7002 9079:7002 9080:7002 9081:7002 9082:7002 9083:7002 9078:7003 9079:7003 9080:7003 9081:7003 9082:7003 9083:7003 9078:7004 9079:7004 9080:7004 9081:7004 9082:7004 9083:7004 9078:7005 9079:7005 9080:7005 9081:7005 9082:7005 9083:7005 9078:7006 9079:7006 9080:7006 9081:7006 9082:7006 9083:7006 9078:7007 9079:7007 9080:7007 9081:7007 9082:7007 9083:7007 9078:7008 9079:7008 9080:7008 9081:7008 9082:7008 9083:7008 9078:7009 9079:7009 9080:7009 9081:7009 9082:7009 9083:7009 9078:7010 9079:7010 9080:7010 9081:7010 9082:7010 9083:7010 9078:7011 9079:7011 9080:7011 9081:7011 9082:7011 9083:7011 9078:7012 9079:7012 9080:7012 9081:7012 9082:7012 9083:7012 9078:7013 9079:7013 9080:7013 9081:7013 9082:7013 9083:7013 9078:7014 9079:7014 9080:7014 9081:7014 9082:7014 9083:7014 9078:7015 9079:7015 9080:7015 9081:7015 9082:7015 9083:7015 9078:7016 9079:7016 9080:7016 9081:7016 9082:7016 9083:7016 9078:7017 9079:7017 9080:7017 9081:7017 9082:7017 9083:7017 9078:7018 9079:7018 9080:7018 9081:7018 9082:7018 9083:7018 9078:7019 9079:7019 9080:7019 9081:7019 9082:7019 9083:7019 9078:7020 9079:7020 9080:7020 9081:7020 9082:7020 9083:7020 9078:7021 9079:7021 9080:7021 9081:7021 9082:7021 9083:7021 9078:7022 9079:7022 9080:7022 9081:7022 9082:7022 9083:7022 9078:7023 9079:7023 9080:7023 9081:7023 9082:7023 9083:7023 9078:7024 9079:7024 9080:7024 9081:7024 9082:7024 9083:7024 9078:7025 9079:7025 9080:7025 9081:7025 9082:7025 9083:7025 9078:7026 9079:7026 9080:7026 9081:7026 9082:7026 9083:7026 9078:7027 9079:7027 9080:7027 9081:7027 9082:7027 9083:7027 9084:7000 9085:7000 9086:7000 9087:7000 9088:7000 9089:7000 9084:7001 9085:7001 9086:7001 9087:7001 9088:7001 9089:7001 9084:7002 9085:7002 9086:7002 9087:7002 9088:7002 9089:7002 9084:7003 9085:7003 9086:7003 9087:7003 9088:7003 9089:7003 9084:7004 9085:7004 9086:7004 9087:7004 9088:7004 9089:7004 9084:7005 9085:7005 9086:7005 9087:7005 9088:7005 9089:7005 9084:7006 9085:7006 9086:7006 9087:7006 9088:7006 9089:7006 9084:7007 9085:7007 9086:7007 9087:7007 9088:7007 9089:7007 9084:7008 9085:7008 9086:7008 9087:7008 9088:7008 9089:7008 9084:7009 9085:7009 9086:7009 9087:7009 9088:7009 9089:7009 9084:7010 9085:7010 9086:7010 9087:7010 9088:7010 9089:7010 9084:7011 9085:7011 9086:7011 9087:7011 9088:7011 9089:7011 9084:7012 9085:7012 9086:7012 9087:7012 9088:7012 9089:7012 9084:7013 9085:7013 9086:7013 9087:7013 9088:7013 9089:7013 9084:7014 9085:7014 9086:7014 9087:7014 9088:7014 9089:7014 9084:7015 9085:7015 9086:7015 9087:7015 9088:7015 9089:7015 9084:7016 9085:7016 9086:7016 9087:7016 9088:7016 9089:7016 9084:7017 9085:7017 9086:7017 9087:7017 9088:7017 9089:7017 9084:7018 9085:7018 9086:7018 9087:7018 9088:7018 9089:7018 9084:7019 9085:7019 9086:7019 9087:7019 9088:7019 9089:7019 9084:7020 9085:7020 9086:7020 9087:7020 9088:7020 9089:7020 9084:7021 9085:7021 9086:7021 9087:7021 9088:7021 9089:7021 9084:7022 9085:7022 9086:7022 9087:7022 9088:7022 9089:7022 9084:7023 9085:7023 9086:7023 9087:7023 9088:7023 9089:7023 9084:7024 9085:7024 9086:7024 9087:7024 9088:7024 9089:7024 9084:7025 9085:7025 9086:7025 9087:7025 9088:7025 9089:7025 9084:7026 9085:7026 9086:7026 9087:7026 9088:7026 9089:7026 9084:7027 9085:7027 9086:7027 9087:7027 9088:7027 9089:7027 9090:7000 9091:7000 9092:7000 9093:7000 9094:7000 9095:7000 9090:7001 9091:7001 9092:7001 9093:7001 9094:7001 9095:7001 9090:7002 9091:7002 9092:7002 9093:7002 9094:7002 9095:7002 9090:7003 9091:7003 9092:7003 9093:7003 9094:7003 9095:7003 9090:7004 9091:7004 9092:7004 9093:7004 9094:7004 9095:7004 9090:7005 9091:7005 9092:7005 9093:7005 9094:7005 9095:7005 9090:7006 9091:7006 9092:7006 9093:7006 9094:7006 9095:7006 9090:7007 9091:7007 9092:7007 9093:7007 9094:7007 9095:7007 9090:7008 9091:7008 9092:7008 9093:7008 9094:7008 9095:7008 9090:7009 9091:7009 9092:7009 9093:7009 9094:7009 9095:7009 9090:7010 9091:7010 9092:7010 9093:7010 9094:7010 9095:7010 9090:7011 9091:7011 9092:7011 9093:7011 9094:7011 9095:7011 9090:7012 9091:7012 9092:7012 9093:7012 9094:7012 9095:7012 9090:7013 9091:7013 9092:7013 9093:7013 9094:7013 9095:7013 9090:7014 9091:7014 9092:7014 9093:7014 9094:7014 9095:7014 9090:7015 9091:7015 9092:7015 9093:7015 9094:7015 9095:7015 9090:7016 9091:7016 9092:7016 9093:7016 9094:7016 9095:7016 9090:7017 9091:7017 9092:7017 9093:7017 9094:7017 9095:7017 9090:7018 9091:7018 9092:7018 9093:7018 9094:7018 9095:7018 9090:7019 9091:7019 9092:7019 9093:7019 9094:7019 9095:7019 9090:7020 9091:7020 9092:7020 9093:7020 9094:7020 9095:7020 9090:7021 9091:7021 9092:7021 9093:7021 9094:7021 9095:7021 9090:7022 9091:7022 9092:7022 9093:7022 9094:7022 9095:7022 9090:7023 9091:7023 9092:7023 9093:7023 9094:7023 9095:7023 9090:7024 9091:7024 9092:7024 9093:7024 9094:7024 9095:7024 9090:7025 9091:7025 9092:7025 9093:7025 9094:7025 9095:7025 9090:7026 9091:7026 9092:7026 9093:7026 9094:7026 9095:7026 9090:7027 9091:7027 9092:7027 9093:7027 9094:7027 9095:7027 9096:7000 9097:7000 9098:7000 9099:7000 9100:7000 9101:7000 9096:7001 9097:7001 9098:7001 9099:7001 9100:7001 9101:7001 9096:7002 9097:7002 9098:7002 9099:7002 9100:7002 9101:7002 9096:7003 9097:7003 9098:7003 9099:7003 9100:7003 9101:7003 9096:7004 9097:7004 9098:7004 9099:7004 9100:7004 9101:7004 9096:7005 9097:7005 9098:7005 9099:7005 9100:7005 9101:7005 9096:7006 9097:7006 9098:7006 9099:7006 9100:7006 9101:7006 9096:7007 9097:7007 9098:7007 9099:7007 9100:7007 9101:7007 9096:7008 9097:7008 9098:7008 9099:7008 9100:7008 9101:7008 9096:7009 9097:7009 9098:7009 9099:7009 9100:7009 9101:7009 9096:7010 9097:7010 9098:7010 9099:7010 9100:7010 9101:7010 9096:7011 9097:7011 9098:7011 9099:7011 9100:7011 9101:7011 9096:7012 9097:7012 9098:7012 9099:7012 9100:7012 9101:7012 9096:7013 9097:7013 9098:7013 9099:7013 9100:7013 9101:7013 9096:7014 9097:7014 9098:7014 9099:7014 9100:7014 9101:7014 9096:7015 9097:7015 9098:7015 9099:7015 9100:7015 9101:7015 9096:7016 9097:7016 9098:7016 9099:7016 9100:7016 9101:7016 9096:7017 9097:7017 9098:7017 9099:7017 9100:7017 9101:7017 9096:7018 9097:7018 9098:7018 9099:7018 9100:7018 9101:7018 9096:7019 9097:7019 9098:7019 9099:7019 9100:7019 9101:7019 9096:7020 9097:7020 9098:7020 9099:7020 9100:7020 9101:7020 9096:7021 9097:7021 9098:7021 9099:7021 9100:7021 9101:7021 9096:7022 9097:7022 9098:7022 9099:7022 9100:7022 9101:7022 9096:7023 9097:7023 9098:7023 9099:7023 9100:7023 9101:7023 9096:7024 9097:7024 9098:7024 9099:7024 9100:7024 9101:7024 9096:7025 9097:7025 9098:7025 9099:7025 9100:7025 9101:7025 9096:7026 9097:7026 9098:7026 9099:7026 9100:7026 9101:7026 9096:7027 9097:7027 9098:7027 9099:7027 9100:7027 9101:7027 9102:7000 9103:7000 9104:7000 9105:7000 — — 9102:7001 9103:7001 9104:7001 9105:7001 9102:7002 9103:7002 9104:7002 9105:7002 9102:7003 9103:7003 9104:7003 9105:7003 9102:7004 9103:7004 9104:7004 9105:7004 9102:7005 9103:7005 9104:7005 9105:7005 9102:7006 9103:7006 9104:7006 9105:7006 9102:7007 9103:7007 9104:7007 9105:7007 9102:7008 9103:7008 9104:7008 9105:7008 9102:7009 9103:7009 9104:7009 9105:7009 9102:7010 9103:7010 9104:7010 9105:7010 9102:7011 9103:7011 9104:7011 9105:7011 9102:7012 9103:7012 9104:7012 9105:7012 9102:7013 9103:7013 9104:7013 9105:7013 9102:7014 9103:7014 9104:7014 9105:7014 9102:7015 9103:7015 9104:7015 9105:7015 9102:7016 9103:7016 9104:7016 9105:7016 9102:7017 9103:7017 9104:7017 9105:7017 9102:7018 9103:7018 9104:7018 9105:7018 9102:7019 9103:7019 9104:7019 9105:7019 9102:7020 9103:7020 9104:7020 9105:7020 9102:7021 9103:7021 9104:7021 9105:7021 9102:7022 9103:7022 9104:7022 9105:7022 9102:7023 9103:7023 9104:7023 9105:7023 9102:7024 9103:7024 9104:7024 9105:7024 9102:7025 9103:7025 9104:7025 9105:7025 9102:7026 9103:7026 9104:7026 9105:7026 9102:7027 9103:7027 9104:7027 9105:7027

TABLE D Example combinations of a compound X with a compound Y. X:Y X:Y X:Y X:Y X:Y X:Y 6000:9000 6040:9000 6000:9001 6040:9001 6000:9002 6040:9002 6001:9000 6041:9000 6001:9001 6041:9001 6001:9002 6041:9002 6002:9000 6042:9000 6002:9001 6042:9001 6002:9002 6042:9002 6003:9000 6043:9000 6003:9001 6043:9001 6003:9002 6043:9002 6004:9000 6044:9000 6004:9001 6044:9001 6004:9002 6044:9002 6005:9000 6045:9000 6005:9001 6045:9001 6005:9002 6045:9002 6006:9000 6046:9000 6006:9001 6046:9001 6006:9002 6046:9002 6007:9000 6047:9000 6007:9001 6047:9001 6007:9002 6047:9002 6008:9000 6048:9000 6008:9001 6048:9001 6008:9002 6048:9002 6009:9000 6049:9000 6009:9001 6049:9001 6009:9002 6049:9002 6010:9000 6050:9000 6010:9001 6050:9001 6010:9002 6050:9002 6011:9000 6051:9000 6011:9001 6051:9001 6011:9002 6051:9002 6012:9000 6052:9000 6012:9001 6052:9001 6012:9002 6052:9002 6013:9000 6053:9000 6013:9001 6053:9001 6013:9002 6053:9002 6014:9000 6054:9000 6014:9001 6054:9001 6014:9002 6054:9002 6015:9000 6055:9000 6015:9001 6055:9001 6015:9002 6055:9002 6016:9000 6056:9000 6016:9001 6056:9001 6016:9002 6056:9002 6017:9000 6057:9000 6017:9001 6057:9001 6017:9002 6057:9002 6018:9000 6058:9000 6018:9001 6058:9001 6018:9002 6058:9002 6019:9000 6059:9000 6019:9001 6059:9001 6019:9002 6059:9002 6020:9000 6060:9000 6020:9001 6060:9001 6020:9002 6060:9002 6021:9000 6061:9000 6021:9001 6061:9001 6021:9002 6061:9002 6022:9000 6062:9000 6022:9001 6062:9001 6022:9002 6062:9002 6023:9000 6063:9000 6023:9001 6063:9001 6023:9002 6063:9002 6024:9000 6064:9000 6024:9001 6064:9001 6024:9002 6064:9002 6025:9000 6065:9000 6025:9001 6065:9001 6025:9002 6065:9002 6026:9000 6066:9000 6026:9001 6066:9001 6026:9002 6066:9002 6027:9000 6067:9000 6027:9001 6067:9001 6027:9002 6067:9002 6028:9000 6068:9000 6028:9001 6068:9001 6028:9002 6068:9002 6029:9000 6069:9000 6029:9001 6069:9001 6029:9002 6069:9002 6030:9000 6070:9000 6030:9001 6070:9001 6030:9002 6070:9002 6031:9000 6071:9000 6031:9001 6071:9001 6031:9002 6071:9002 6032:9000 6072:9000 6032:9001 6072:9001 6032:9002 6072:9002 6033:9000 6073:9000 6033:9001 6073:9001 6033:9002 6073:9002 6034:9000 6074:9000 6034:9001 6074:9001 6034:9002 6074:9002 6035:9000 6075:9000 6035:9001 6075:9001 6035:9002 6075:9002 6036:9000 6076:9000 6036:9001 6076:9001 6036:9002 6076:9002 6037:9000 6077:9000 6037:9001 6077:9001 6037:9002 6077:9002 6038:9000 6078:9000 6038:9001 6078:9001 6038:9002 6078:9002 6039:9000 6039:9001 6039:9002 6000:9003 6040:9003 6000:9004 6040:9004 6000:9005 6040:9005 6001:9003 6041:9003 6001:9004 6041:9004 6001:9005 6041:9005 6002:9003 6042:9003 6002:9004 6042:9004 6002:9005 6042:9005 6003:9003 6043:9003 6003:9004 6043:9004 6003:9005 6043:9005 6004:9003 6044:9003 6004:9004 6044:9004 6004:9005 6044:9005 6005:9003 6045:9003 6005:9004 6045:9004 6005:9005 6045:9005 6006:9003 6046:9003 6006:9004 6046:9004 6006:9005 6046:9005 6007:9003 6047:9003 6007:9004 6047:9004 6007:9005 6047:9005 6008:9003 6048:9003 6008:9004 6048:9004 6008:9005 6048:9005 6009:9003 6049:9003 6009:9004 6049:9004 6009:9005 6049:9005 6010:9003 6050:9003 6010:9004 6050:9004 6010:9005 6050:9005 6011:9003 6051:9003 6011:9004 6051:9004 6011:9005 6051:9005 6012:9003 6052:9003 6012:9004 6052:9004 6012:9005 6052:9005 6013:9003 6053:9003 6013:9004 6053:9004 6013:9005 6053:9005 6014:9003 6054:9003 6014:9004 6054:9004 6014:9005 6054:9005 6015:9003 6055:9003 6015:9004 6055:9004 6015:9005 6055:9005 6016:9003 6056:9003 6016:9004 6056:9004 6016:9005 6056:9005 6017:9003 6057:9003 6017:9004 6057:9004 6017:9005 6057:9005 6018:9003 6058:9003 6018:9004 6058:9004 6018:9005 6058:9005 6019:9003 6059:9003 6019:9004 6059:9004 6019:9005 6059:9005 6020:9003 6060:9003 6020:9004 6060:9004 6020:9005 6060:9005 6021:9003 6061:9003 6021:9004 6061:9004 6021:9005 6061:9005 6022:9003 6062:9003 6022:9004 6062:9004 6022:9005 6062:9005 6023:9003 6063:9003 6023:9004 6063:9004 6023:9005 6063:9005 6024:9003 6064:9003 6024:9004 6064:9004 6024:9005 6064:9005 6025:9003 6065:9003 6025:9004 6065:9004 6025:9005 6065:9005 6026:9003 6066:9003 6026:9004 6066:9004 6026:9005 6066:9005 6027:9003 6067:9003 6027:9004 6067:9004 6027:9005 6067:9005 6028:9003 6068:9003 6028:9004 6068:9004 6028:9005 6068:9005 6029:9003 6069:9003 6029:9004 6069:9004 6029:9005 6069:9005 6030:9003 6070:9003 6030:9004 6070:9004 6030:9005 6070:9005 6031:9003 6071:9003 6031:9004 6071:9004 6031:9005 6071:9005 6032:9003 6072:9003 6032:9004 6072:9004 6032:9005 6072:9005 6033:9003 6073:9003 6033:9004 6073:9004 6033:9005 6073:9005 6034:9003 6074:9003 6034:9004 6074:9004 6034:9005 6074:9005 6035:9003 6075:9003 6035:9004 6075:9004 6035:9005 6075:9005 6036:9003 6076:9003 6036:9004 6076:9004 6036:9005 6076:9005 6037:9003 6077:9003 6037:9004 6077:9004 6037:9005 6077:9005 6038:9003 6078:9003 6038:9004 6078:9004 6038:9005 6078:9005 6039:9003 6039:9004 6039:9005 6000:9006 6040:9006 6000:9007 6040:9007 6000:9008 6040:9008 6001:9006 6041:9006 6001:9007 6041:9007 6001:9008 6041:9008 6002:9006 6042:9006 6002:9007 6042:9007 6002:9008 6042:9008 6003:9006 6043:9006 6003:9007 6043:9007 6003:9008 6043:9008 6004:9006 6044:9006 6004:9007 6044:9007 6004:9008 6044:9008 6005:9006 6045:9006 6005:9007 6045:9007 6005:9008 6045:9008 6006:9006 6046:9006 6006:9007 6046:9007 6006:9008 6046:9008 6007:9006 6047:9006 6007:9007 6047:9007 6007:9008 6047:9008 6008:9006 6048:9006 6008:9007 6048:9007 6008:9008 6048:9008 6009:9006 6049:9006 6009:9007 6049:9007 6009:9008 6049:9008 6010:9006 6050:9006 6010:9007 6050:9007 6010:9008 6050:9008 6011:9006 6051:9006 6011:9007 6051:9007 6011:9008 6051:9008 6012:9006 6052:9006 6012:9007 6052:9007 6012:9008 6052:9008 6013:9006 6053:9006 6013:9007 6053:9007 6013:9008 6053:9008 6014:9006 6054:9006 6014:9007 6054:9007 6014:9008 6054:9008 6015:9006 6055:9006 6015:9007 6055:9007 6015:9008 6055:9008 6016:9006 6056:9006 6016:9007 6056:9007 6016:9008 6056:9008 6017:9006 6057:9006 6017:9007 6057:9007 6017:9008 6057:9008 6018:9006 6058:9006 6018:9007 6058:9007 6018:9008 6058:9008 6019:9006 6059:9006 6019:9007 6059:9007 6019:9008 6059:9008 6020:9006 6060:9006 6020:9007 6060:9007 6020:9008 6060:9008 6021:9006 6061:9006 6021:9007 6061:9007 6021:9008 6061:9008 6022:9006 6062:9006 6022:9007 6062:9007 6022:9008 6062:9008 6023:9006 6063:9006 6023:9007 6063:9007 6023:9008 6063:9008 6024:9006 6064:9006 6024:9007 6064:9007 6024:9008 6064:9008 6025:9006 6065:9006 6025:9007 6065:9007 6025:9008 6065:9008 6026:9006 6066:9006 6026:9007 6066:9007 6026:9008 6066:9008 6027:9006 6067:9006 6027:9007 6067:9007 6027:9008 6067:9008 6028:9006 6068:9006 6028:9007 6068:9007 6028:9008 6068:9008 6029:9006 6069:9006 6029:9007 6069:9007 6029:9008 6069:9008 6030:9006 6070:9006 6030:9007 6070:9007 6030:9008 6070:9008 6031:9006 6071:9006 6031:9007 6071:9007 6031:9008 6071:9008 6032:9006 6072:9006 6032:9007 6072:9007 6032:9008 6072:9008 6033:9006 6073:9006 6033:9007 6073:9007 6033:9008 6073:9008 6034:9006 6074:9006 6034:9007 6074:9007 6034:9008 6074:9008 6035:9006 6075:9006 6035:9007 6075:9007 6035:9008 6075:9008 6036:9006 6076:9006 6036:9007 6076:9007 6036:9008 6076:9008 6037:9006 6077:9006 6037:9007 6077:9007 6037:9008 6077:9008 6038:9006 6078:9006 6038:9007 6078:9007 6038:9008 6078:9008 6039:9006 6039:9007 6039:9008 6000:9009 6040:9009 6000:9010 6040:9010 6000:9011 6040:9011 6001:9009 6041:9009 6001:9010 6041:9010 6001:9011 6041:9011 6002:9009 6042:9009 6002:9010 6042:9010 6002:9011 6042:9011 6003:9009 6043:9009 6003:9010 6043:9010 6003:9011 6043:9011 6004:9009 6044:9009 6004:9010 6044:9010 6004:9011 6044:9011 6005:9009 6045:9009 6005:9010 6045:9010 6005:9011 6045:9011 6006:9009 6046:9009 6006:9010 6046:9010 6006:9011 6046:9011 6007:9009 6047:9009 6007:9010 6047:9010 6007:9011 6047:9011 6008:9009 6048:9009 6008:9010 6048:9010 6008:9011 6048:9011 6009:9009 6049:9009 6009:9010 6049:9010 6009:9011 6049:9011 6010:9009 6050:9009 6010:9010 6050:9010 6010:9011 6050:9011 6011:9009 6051:9009 6011:9010 6051:9010 6011:9011 6051:9011 6012:9009 6052:9009 6012:9010 6052:9010 6012:9011 6052:9011 6013:9009 6053:9009 6013:9010 6053:9010 6013:9011 6053:9011 6014:9009 6054:9009 6014:9010 6054:9010 6014:9011 6054:9011 6015:9009 6055:9009 6015:9010 6055:9010 6015:9011 6055:9011 6016:9009 6056:9009 6016:9010 6056:9010 6016:9011 6056:9011 6017:9009 6057:9009 6017:9010 6057:9010 6017:9011 6057:9011 6018:9009 6058:9009 6018:9010 6058:9010 6018:9011 6058:9011 6019:9009 6059:9009 6019:9010 6059:9010 6019:9011 6059:9011 6020:9009 6060:9009 6020:9010 6060:9010 6020:9011 6060:9011 6021:9009 6061:9009 6021:9010 6061:9010 6021:9011 6061:9011 6022:9009 6062:9009 6022:9010 6062:9010 6022:9011 6062:9011 6023:9009 6063:9009 6023:9010 6063:9010 6023:9011 6063:9011 6024:9009 6064:9009 6024:9010 6064:9010 6024:9011 6064:9011 6025:9009 6065:9009 6025:9010 6065:9010 6025:9011 6065:9011 6026:9009 6066:9009 6026:9010 6066:9010 6026:9011 6066:9011 6027:9009 6067:9009 6027:9010 6067:9010 6027:9011 6067:9011 6028:9009 6068:9009 6028:9010 6068:9010 6028:9011 6068:9011 6029:9009 6069:9009 6029:9010 6069:9010 6029:9011 6069:9011 6030:9009 6070:9009 6030:9010 6070:9010 6030:9011 6070:9011 6031:9009 6071:9009 6031:9010 6071:9010 6031:9011 6071:9011 6032:9009 6072:9009 6032:9010 6072:9010 6032:9011 6072:9011 6033:9009 6073:9009 6033:9010 6073:9010 6033:9011 6073:9011 6034:9009 6074:9009 6034:9010 6074:9010 6034:9011 6074:9011 6035:9009 6075:9009 6035:9010 6075:9010 6035:9011 6075:9011 6036:9009 6076:9009 6036:9010 6076:9010 6036:9011 6076:9011 6037:9009 6077:9009 6037:9010 6077:9010 6037:9011 6077:9011 6038:9009 6078:9009 6038:9010 6078:9010 6038:9011 6078:9011 6039:9009 6039:9010 6039:9011 6000:9012 6040:9012 6000:9013 6040:9013 6000:9014 6040:9014 6001:9012 6041:9012 6001:9013 6041:9013 6001:9014 6041:9014 6002:9012 6042:9012 6002:9013 6042:9013 6002:9014 6042:9014 6003:9012 6043:9012 6003:9013 6043:9013 6003:9014 6043:9014 6004:9012 6044:9012 6004:9013 6044:9013 6004:9014 6044:9014 6005:9012 6045:9012 6005:9013 6045:9013 6005:9014 6045:9014 6006:9012 6046:9012 6006:9013 6046:9013 6006:9014 6046:9014 6007:9012 6047:9012 6007:9013 6047:9013 6007:9014 6047:9014 6008:9012 6048:9012 6008:9013 6048:9013 6008:9014 6048:9014 6009:9012 6049:9012 6009:9013 6049:9013 6009:9014 6049:9014 6010:9012 6050:9012 6010:9013 6050:9013 6010:9014 6050:9014 6011:9012 6051:9012 6011:9013 6051:9013 6011:9014 6051:9014 6012:9012 6052:9012 6012:9013 6052:9013 6012:9014 6052:9014 6013:9012 6053:9012 6013:9013 6053:9013 6013:9014 6053:9014 6014:9012 6054:9012 6014:9013 6054:9013 6014:9014 6054:9014 6015:9012 6055:9012 6015:9013 6055:9013 6015:9014 6055:9014 6016:9012 6056:9012 6016:9013 6056:9013 6016:9014 6056:9014 6017:9012 6057:9012 6017:9013 6057:9013 6017:9014 6057:9014 6018:9012 6058:9012 6018:9013 6058:9013 6018:9014 6058:9014 6019:9012 6059:9012 6019:9013 6059:9013 6019:9014 6059:9014 6020:9012 6060:9012 6020:9013 6060:9013 6020:9014 6060:9014 6021:9012 6061:9012 6021:9013 6061:9013 6021:9014 6061:9014 6022:9012 6062:9012 6022:9013 6062:9013 6022:9014 6062:9014 6023:9012 6063:9012 6023:9013 6063:9013 6023:9014 6063:9014 6024:9012 6064:9012 6024:9013 6064:9013 6024:9014 6064:9014 6025:9012 6065:9012 6025:9013 6065:9013 6025:9014 6065:9014 6026:9012 6066:9012 6026:9013 6066:9013 6026:9014 6066:9014 6027:9012 6067:9012 6027:9013 6067:9013 6027:9014 6067:9014 6028:9012 6068:9012 6028:9013 6068:9013 6028:9014 6068:9014 6029:9012 6069:9012 6029:9013 6069:9013 6029:9014 6069:9014 6030:9012 6070:9012 6030:9013 6070:9013 6030:9014 6070:9014 6031:9012 6071:9012 6031:9013 6071:9013 6031:9014 6071:9014 6032:9012 6072:9012 6032:9013 6072:9013 6032:9014 6072:9014 6033:9012 6073:9012 6033:9013 6073:9013 6033:9014 6073:9014 6034:9012 6074:9012 6034:9013 6074:9013 6034:9014 6074:9014 6035:9012 6075:9012 6035:9013 6075:9013 6035:9014 6075:9014 6036:9012 6076:9012 6036:9013 6076:9013 6036:9014 6076:9014 6037:9012 6077:9012 6037:9013 6077:9013 6037:9014 6077:9014 6038:9012 6078:9012 6038:9013 6078:9013 6038:9014 6078:9014 6039:9012 6039:9013 6039:9014 6000:9015 6040:9015 6000:9016 6040:9016 6000:9017 6040:9017 6001:9015 6041:9015 6001:9016 6041:9016 6001:9017 6041:9017 6002:9015 6042:9015 6002:9016 6042:9016 6002:9017 6042:9017 6003:9015 6043:9015 6003:9016 6043:9016 6003:9017 6043:9017 6004:9015 6044:9015 6004:9016 6044:9016 6004:9017 6044:9017 6005:9015 6045:9015 6005:9016 6045:9016 6005:9017 6045:9017 6006:9015 6046:9015 6006:9016 6046:9016 6006:9017 6046:9017 6007:9015 6047:9015 6007:9016 6047:9016 6007:9017 6047:9017 6008:9015 6048:9015 6008:9016 6048:9016 6008:9017 6048:9017 6009:9015 6049:9015 6009:9016 6049:9016 6009:9017 6049:9017 6010:9015 6050:9015 6010:9016 6050:9016 6010:9017 6050:9017 6011:9015 6051:9015 6011:9016 6051:9016 6011:9017 6051:9017 6012:9015 6052:9015 6012:9016 6052:9016 6012:9017 6052:9017 6013:9015 6053:9015 6013:9016 6053:9016 6013:9017 6053:9017 6014:9015 6054:9015 6014:9016 6054:9016 6014:9017 6054:9017 6015:9015 6055:9015 6015:9016 6055:9016 6015:9017 6055:9017 6016:9015 6056:9015 6016:9016 6056:9016 6016:9017 6056:9017 6017:9015 6057:9015 6017:9016 6057:9016 6017:9017 6057:9017 6018:9015 6058:9015 6018:9016 6058:9016 6018:9017 6058:9017 6019:9015 6059:9015 6019:9016 6059:9016 6019:9017 6059:9017 6020:9015 6060:9015 6020:9016 6060:9016 6020:9017 6060:9017 6021:9015 6061:9015 6021:9016 6061:9016 6021:9017 6061:9017 6022:9015 6062:9015 6022:9016 6062:9016 6022:9017 6062:9017 6023:9015 6063:9015 6023:9016 6063:9016 6023:9017 6063:9017 6024:9015 6064:9015 6024:9016 6064:9016 6024:9017 6064:9017 6025:9015 6065:9015 6025:9016 6065:9016 6025:9017 6065:9017 6026:9015 6066:9015 6026:9016 6066:9016 6026:9017 6066:9017 6027:9015 6067:9015 6027:9016 6067:9016 6027:9017 6067:9017 6028:9015 6068:9015 6028:9016 6068:9016 6028:9017 6068:9017 6029:9015 6069:9015 6029:9016 6069:9016 6029:9017 6069:9017 6030:9015 6070:9015 6030:9016 6070:9016 6030:9017 6070:9017 6031:9015 6071:9015 6031:9016 6071:9016 6031:9017 6071:9017 6032:9015 6072:9015 6032:9016 6072:9016 6032:9017 6072:9017 6033:9015 6073:9015 6033:9016 6073:9016 6033:9017 6073:9017 6034:9015 6074:9015 6034:9016 6074:9016 6034:9017 6074:9017 6035:9015 6075:9015 6035:9016 6075:9016 6035:9017 6075:9017 6036:9015 6076:9015 6036:9016 6076:9016 6036:9017 6076:9017 6037:9015 6077:9015 6037:9016 6077:9016 6037:9017 6077:9017 6038:9015 6078:9015 6038:9016 6078:9016 6038:9017 6078:9017 6039:9015 6039:9016 6039:9017 6000:9018 6040:9018 6000:9019 6040:9019 6000:9020 6040:9020 6001:9018 6041:9018 6001:9019 6041:9019 6001:9020 6041:9020 6002:9018 6042:9018 6002:9019 6042:9019 6002:9020 6042:9020 6003:9018 6043:9018 6003:9019 6043:9019 6003:9020 6043:9020 6004:9018 6044:9018 6004:9019 6044:9019 6004:9020 6044:9020 6005:9018 6045:9018 6005:9019 6045:9019 6005:9020 6045:9020 6006:9018 6046:9018 6006:9019 6046:9019 6006:9020 6046:9020 6007:9018 6047:9018 6007:9019 6047:9019 6007:9020 6047:9020 6008:9018 6048:9018 6008:9019 6048:9019 6008:9020 6048:9020 6009:9018 6049:9018 6009:9019 6049:9019 6009:9020 6049:9020 6010:9018 6050:9018 6010:9019 6050:9019 6010:9020 6050:9020 6011:9018 6051:9018 6011:9019 6051:9019 6011:9020 6051:9020 6012:9018 6052:9018 6012:9019 6052:9019 6012:9020 6052:9020 6013:9018 6053:9018 6013:9019 6053:9019 6013:9020 6053:9020 6014:9018 6054:9018 6014:9019 6054:9019 6014:9020 6054:9020 6015:9018 6055:9018 6015:9019 6055:9019 6015:9020 6055:9020 6016:9018 6056:9018 6016:9019 6056:9019 6016:9020 6056:9020 6017:9018 6057:9018 6017:9019 6057:9019 6017:9020 6057:9020 6018:9018 6058:9018 6018:9019 6058:9019 6018:9020 6058:9020 6019:9018 6059:9018 6019:9019 6059:9019 6019:9020 6059:9020 6020:9018 6060:9018 6020:9019 6060:9019 6020:9020 6060:9020 6021:9018 6061:9018 6021:9019 6061:9019 6021:9020 6061:9020 6022:9018 6062:9018 6022:9019 6062:9019 6022:9020 6062:9020 6023:9018 6063:9018 6023:9019 6063:9019 6023:9020 6063:9020 6024:9018 6064:9018 6024:9019 6064:9019 6024:9020 6064:9020 6025:9018 6065:9018 6025:9019 6065:9019 6025:9020 6065:9020 6026:9018 6066:9018 6026:9019 6066:9019 6026:9020 6066:9020 6027:9018 6067:9018 6027:9019 6067:9019 6027:9020 6067:9020 6028:9018 6068:9018 6028:9019 6068:9019 6028:9020 6068:9020 6029:9018 6069:9018 6029:9019 6069:9019 6029:9020 6069:9020 6030:9018 6070:9018 6030:9019 6070:9019 6030:9020 6070:9020 6031:9018 6071:9018 6031:9019 6071:9019 6031:9020 6071:9020 6032:9018 6072:9018 6032:9019 6072:9019 6032:9020 6072:9020 6033:9018 6073:9018 6033:9019 6073:9019 6033:9020 6073:9020 6034:9018 6074:9018 6034:9019 6074:9019 6034:9020 6074:9020 6035:9018 6075:9018 6035:9019 6075:9019 6035:9020 6075:9020 6036:9018 6076:9018 6036:9019 6076:9019 6036:9020 6076:9020 6037:9018 6077:9018 6037:9019 6077:9019 6037:9020 6077:9020 6038:9018 6078:9018 6038:9019 6078:9019 6038:9020 6078:9020 6039:9018 6039:9019 6039:9020 6000:9021 6040:9021 6000:9022 6040:9022 6000:9023 6040:9023 6001:9021 6041:9021 6001:9022 6041:9022 6001:9023 6041:9023 6002:9021 6042:9021 6002:9022 6042:9022 6002:9023 6042:9023 6003:9021 6043:9021 6003:9022 6043:9022 6003:9023 6043:9023 6004:9021 6044:9021 6004:9022 6044:9022 6004:9023 6044:9023 6005:9021 6045:9021 6005:9022 6045:9022 6005:9023 6045:9023 6006:9021 6046:9021 6006:9022 6046:9022 6006:9023 6046:9023 6007:9021 6047:9021 6007:9022 6047:9022 6007:9023 6047:9023 6008:9021 6048:9021 6008:9022 6048:9022 6008:9023 6048:9023 6009:9021 6049:9021 6009:9022 6049:9022 6009:9023 6049:9023 6010:9021 6050:9021 6010:9022 6050:9022 6010:9023 6050:9023 6011:9021 6051:9021 6011:9022 6051:9022 6011:9023 6051:9023 6012:9021 6052:9021 6012:9022 6052:9022 6012:9023 6052:9023 6013:9021 6053:9021 6013:9022 6053:9022 6013:9023 6053:9023 6014:9021 6054:9021 6014:9022 6054:9022 6014:9023 6054:9023 6015:9021 6055:9021 6015:9022 6055:9022 6015:9023 6055:9023 6016:9021 6056:9021 6016:9022 6056:9022 6016:9023 6056:9023 6017:9021 6057:9021 6017:9022 6057:9022 6017:9023 6057:9023 6018:9021 6058:9021 6018:9022 6058:9022 6018:9023 6058:9023 6019:9021 6059:9021 6019:9022 6059:9022 6019:9023 6059:9023 6020:9021 6060:9021 6020:9022 6060:9022 6020:9023 6060:9023 6021:9021 6061:9021 6021:9022 6061:9022 6021:9023 6061:9023 6022:9021 6062:9021 6022:9022 6062:9022 6022:9023 6062:9023 6023:9021 6063:9021 6023:9022 6063:9022 6023:9023 6063:9023 6024:9021 6064:9021 6024:9022 6064:9022 6024:9023 6064:9023 6025:9021 6065:9021 6025:9022 6065:9022 6025:9023 6065:9023 6026:9021 6066:9021 6026:9022 6066:9022 6026:9023 6066:9023 6027:9021 6067:9021 6027:9022 6067:9022 6027:9023 6067:9023 6028:9021 6068:9021 6028:9022 6068:9022 6028:9023 6068:9023 6029:9021 6069:9021 6029:9022 6069:9022 6029:9023 6069:9023 6030:9021 6070:9021 6030:9022 6070:9022 6030:9023 6070:9023 6031:9021 6071:9021 6031:9022 6071:9022 6031:9023 6071:9023 6032:9021 6072:9021 6032:9022 6072:9022 6032:9023 6072:9023 6033:9021 6073:9021 6033:9022 6073:9022 6033:9023 6073:9023 6034:9021 6074:9021 6034:9022 6074:9022 6034:9023 6074:9023 6035:9021 6075:9021 6035:9022 6075:9022 6035:9023 6075:9023 6036:9021 6076:9021 6036:9022 6076:9022 6036:9023 6076:9023 6037:9021 6077:9021 6037:9022 6077:9022 6037:9023 6077:9023 6038:9021 6078:9021 6038:9022 6078:9022 6038:9023 6078:9023 6039:9021 6039:9022 6039:9023 6000:9024 6040:9024 6000:9025 6040:9025 6000:9026 6040:9026 6001:9024 6041:9024 6001:9025 6041:9025 6001:9026 6041:9026 6002:9024 6042:9024 6002:9025 6042:9025 6002:9026 6042:9026 6003:9024 6043:9024 6003:9025 6043:9025 6003:9026 6043:9026 6004:9024 6044:9024 6004:9025 6044:9025 6004:9026 6044:9026 6005:9024 6045:9024 6005:9025 6045:9025 6005:9026 6045:9026 6006:9024 6046:9024 6006:9025 6046:9025 6006:9026 6046:9026 6007:9024 6047:9024 6007:9025 6047:9025 6007:9026 6047:9026 6008:9024 6048:9024 6008:9025 6048:9025 6008:9026 6048:9026 6009:9024 6049:9024 6009:9025 6049:9025 6009:9026 6049:9026 6010:9024 6050:9024 6010:9025 6050:9025 6010:9026 6050:9026 6011:9024 6051:9024 6011:9025 6051:9025 6011:9026 6051:9026 6012:9024 6052:9024 6012:9025 6052:9025 6012:9026 6052:9026 6013:9024 6053:9024 6013:9025 6053:9025 6013:9026 6053:9026 6014:9024 6054:9024 6014:9025 6054:9025 6014:9026 6054:9026 6015:9024 6055:9024 6015:9025 6055:9025 6015:9026 6055:9026 6016:9024 6056:9024 6016:9025 6056:9025 6016:9026 6056:9026 6017:9024 6057:9024 6017:9025 6057:9025 6017:9026 6057:9026 6018:9024 6058:9024 6018:9025 6058:9025 6018:9026 6058:9026 6019:9024 6059:9024 6019:9025 6059:9025 6019:9026 6059:9026 6020:9024 6060:9024 6020:9025 6060:9025 6020:9026 6060:9026 6021:9024 6061:9024 6021:9025 6061:9025 6021:9026 6061:9026 6022:9024 6062:9024 6022:9025 6062:9025 6022:9026 6062:9026 6023:9024 6063:9024 6023:9025 6063:9025 6023:9026 6063:9026 6024:9024 6064:9024 6024:9025 6064:9025 6024:9026 6064:9026 6025:9024 6065:9024 6025:9025 6065:9025 6025:9026 6065:9026 6026:9024 6066:9024 6026:9025 6066:9025 6026:9026 6066:9026 6027:9024 6067:9024 6027:9025 6067:9025 6027:9026 6067:9026 6028:9024 6068:9024 6028:9025 6068:9025 6028:9026 6068:9026 6029:9024 6069:9024 6029:9025 6069:9025 6029:9026 6069:9026 6030:9024 6070:9024 6030:9025 6070:9025 6030:9026 6070:9026 6031:9024 6071:9024 6031:9025 6071:9025 6031:9026 6071:9026 6032:9024 6072:9024 6032:9025 6072:9025 6032:9026 6072:9026 6033:9024 6073:9024 6033:9025 6073:9025 6033:9026 6073:9026 6034:9024 6074:9024 6034:9025 6074:9025 6034:9026 6074:9026 6035:9024 6075:9024 6035:9025 6075:9025 6035:9026 6075:9026 6036:9024 6076:9024 6036:9025 6076:9025 6036:9026 6076:9026 6037:9024 6077:9024 6037:9025 6077:9025 6037:9026 6077:9026 6038:9024 6078:9024 6038:9025 6078:9025 6038:9026 6078:9026 6039:9024 6039:9025 6039:9026 6000:9027 6040:9027 6000:9028 6040:9028 6000:9029 6040:9029 6001:9027 6041:9027 6001:9028 6041:9028 6001:9029 6041:9029 6002:9027 6042:9027 6002:9028 6042:9028 6002:9029 6042:9029 6003:9027 6043:9027 6003:9028 6043:9028 6003:9029 6043:9029 6004:9027 6044:9027 6004:9028 6044:9028 6004:9029 6044:9029 6005:9027 6045:9027 6005:9028 6045:9028 6005:9029 6045:9029 6006:9027 6046:9027 6006:9028 6046:9028 6006:9029 6046:9029 6007:9027 6047:9027 6007:9028 6047:9028 6007:9029 6047:9029 6008:9027 6048:9027 6008:9028 6048:9028 6008:9029 6048:9029 6009:9027 6049:9027 6009:9028 6049:9028 6009:9029 6049:9029 6010:9027 6050:9027 6010:9028 6050:9028 6010:9029 6050:9029 6011:9027 6051:9027 6011:9028 6051:9028 6011:9029 6051:9029 6012:9027 6052:9027 6012:9028 6052:9028 6012:9029 6052:9029 6013:9027 6053:9027 6013:9028 6053:9028 6013:9029 6053:9029 6014:9027 6054:9027 6014:9028 6054:9028 6014:9029 6054:9029 6015:9027 6055:9027 6015:9028 6055:9028 6015:9029 6055:9029 6016:9027 6056:9027 6016:9028 6056:9028 6016:9029 6056:9029 6017:9027 6057:9027 6017:9028 6057:9028 6017:9029 6057:9029 6018:9027 6058:9027 6018:9028 6058:9028 6018:9029 6058:9029 6019:9027 6059:9027 6019:9028 6059:9028 6019:9029 6059:9029 6020:9027 6060:9027 6020:9028 6060:9028 6020:9029 6060:9029 6021:9027 6061:9027 6021:9028 6061:9028 6021:9029 6061:9029 6022:9027 6062:9027 6022:9028 6062:9028 6022:9029 6062:9029 6023:9027 6063:9027 6023:9028 6063:9028 6023:9029 6063:9029 6024:9027 6064:9027 6024:9028 6064:9028 6024:9029 6064:9029 6025:9027 6065:9027 6025:9028 6065:9028 6025:9029 6065:9029 6026:9027 6066:9027 6026:9028 6066:9028 6026:9029 6066:9029 6027:9027 6067:9027 6027:9028 6067:9028 6027:9029 6067:9029 6028:9027 6068:9027 6028:9028 6068:9028 6028:9029 6068:9029 6029:9027 6069:9027 6029:9028 6069:9028 6029:9029 6069:9029 6030:9027 6070:9027 6030:9028 6070:9028 6030:9029 6070:9029 6031:9027 6071:9027 6031:9028 6071:9028 6031:9029 6071:9029 6032:9027 6072:9027 6032:9028 6072:9028 6032:9029 6072:9029 6033:9027 6073:9027 6033:9028 6073:9028 6033:9029 6073:9029 6034:9027 6074:9027 6034:9028 6074:9028 6034:9029 6074:9029 6035:9027 6075:9027 6035:9028 6075:9028 6035:9029 6075:9029 6036:9027 6076:9027 6036:9028 6076:9028 6036:9029 6076:9029 6037:9027 6077:9027 6037:9028 6077:9028 6037:9029 6077:9029 6038:9027 6078:9027 6038:9028 6078:9028 6038:9029 6078:9029 6039:9027 6039:9028 6039:9029 6000:9030 6040:9030 6000:9031 6040:9031 6000:9032 6040:9032 6001:9030 6041:9030 6001:9031 6041:9031 6001:9032 6041:9032 6002:9030 6042:9030 6002:9031 6042:9031 6002:9032 6042:9032 6003:9030 6043:9030 6003:9031 6043:9031 6003:9032 6043:9032 6004:9030 6044:9030 6004:9031 6044:9031 6004:9032 6044:9032 6005:9030 6045:9030 6005:9031 6045:9031 6005:9032 6045:9032 6006:9030 6046:9030 6006:9031 6046:9031 6006:9032 6046:9032 6007:9030 6047:9030 6007:9031 6047:9031 6007:9032 6047:9032 6008:9030 6048:9030 6008:9031 6048:9031 6008:9032 6048:9032 6009:9030 6049:9030 6009:9031 6049:9031 6009:9032 6049:9032 6010:9030 6050:9030 6010:9031 6050:9031 6010:9032 6050:9032 6011:9030 6051:9030 6011:9031 6051:9031 6011:9032 6051:9032 6012:9030 6052:9030 6012:9031 6052:9031 6012:9032 6052:9032 6013:9030 6053:9030 6013:9031 6053:9031 6013:9032 6053:9032 6014:9030 6054:9030 6014:9031 6054:9031 6014:9032 6054:9032 6015:9030 6055:9030 6015:9031 6055:9031 6015:9032 6055:9032 6016:9030 6056:9030 6016:9031 6056:9031 6016:9032 6056:9032 6017:9030 6057:9030 6017:9031 6057:9031 6017:9032 6057:9032 6018:9030 6058:9030 6018:9031 6058:9031 6018:9032 6058:9032 6019:9030 6059:9030 6019:9031 6059:9031 6019:9032 6059:9032 6020:9030 6060:9030 6020:9031 6060:9031 6020:9032 6060:9032 6021:9030 6061:9030 6021:9031 6061:9031 6021:9032 6061:9032 6022:9030 6062:9030 6022:9031 6062:9031 6022:9032 6062:9032 6023:9030 6063:9030 6023:9031 6063:9031 6023:9032 6063:9032 6024:9030 6064:9030 6024:9031 6064:9031 6024:9032 6064:9032 6025:9030 6065:9030 6025:9031 6065:9031 6025:9032 6065:9032 6026:9030 6066:9030 6026:9031 6066:9031 6026:9032 6066:9032 6027:9030 6067:9030 6027:9031 6067:9031 6027:9032 6067:9032 6028:9030 6068:9030 6028:9031 6068:9031 6028:9032 6068:9032 6029:9030 6069:9030 6029:9031 6069:9031 6029:9032 6069:9032 6030:9030 6070:9030 6030:9031 6070:9031 6030:9032 6070:9032 6031:9030 6071:9030 6031:9031 6071:9031 6031:9032 6071:9032 6032:9030 6072:9030 6032:9031 6072:9031 6032:9032 6072:9032 6033:9030 6073:9030 6033:9031 6073:9031 6033:9032 6073:9032 6034:9030 6074:9030 6034:9031 6074:9031 6034:9032 6074:9032 6035:9030 6075:9030 6035:9031 6075:9031 6035:9032 6075:9032 6036:9030 6076:9030 6036:9031 6076:9031 6036:9032 6076:9032 6037:9030 6077:9030 6037:9031 6077:9031 6037:9032 6077:9032 6038:9030 6078:9030 6038:9031 6078:9031 6038:9032 6078:9032 6039:9030 6039:9031 6039:9032 6000:9033 6040:9033 6000:9034 6040:9034 6000:9035 6040:9035 6001:9033 6041:9033 6001:9034 6041:9034 6001:9035 6041:9035 6002:9033 6042:9033 6002:9034 6042:9034 6002:9035 6042:9035 6003:9033 6043:9033 6003:9034 6043:9034 6003:9035 6043:9035 6004:9033 6044:9033 6004:9034 6044:9034 6004:9035 6044:9035 6005:9033 6045:9033 6005:9034 6045:9034 6005:9035 6045:9035 6006:9033 6046:9033 6006:9034 6046:9034 6006:9035 6046:9035 6007:9033 6047:9033 6007:9034 6047:9034 6007:9035 6047:9035 6008:9033 6048:9033 6008:9034 6048:9034 6008:9035 6048:9035 6009:9033 6049:9033 6009:9034 6049:9034 6009:9035 6049:9035 6010:9033 6050:9033 6010:9034 6050:9034 6010:9035 6050:9035 6011:9033 6051:9033 6011:9034 6051:9034 6011:9035 6051:9035 6012:9033 6052:9033 6012:9034 6052:9034 6012:9035 6052:9035 6013:9033 6053:9033 6013:9034 6053:9034 6013:9035 6053:9035 6014:9033 6054:9033 6014:9034 6054:9034 6014:9035 6054:9035 6015:9033 6055:9033 6015:9034 6055:9034 6015:9035 6055:9035 6016:9033 6056:9033 6016:9034 6056:9034 6016:9035 6056:9035 6017:9033 6057:9033 6017:9034 6057:9034 6017:9035 6057:9035 6018:9033 6058:9033 6018:9034 6058:9034 6018:9035 6058:9035 6019:9033 6059:9033 6019:9034 6059:9034 6019:9035 6059:9035 6020:9033 6060:9033 6020:9034 6060:9034 6020:9035 6060:9035 6021:9033 6061:9033 6021:9034 6061:9034 6021:9035 6061:9035 6022:9033 6062:9033 6022:9034 6062:9034 6022:9035 6062:9035 6023:9033 6063:9033 6023:9034 6063:9034 6023:9035 6063:9035 6024:9033 6064:9033 6024:9034 6064:9034 6024:9035 6064:9035 6025:9033 6065:9033 6025:9034 6065:9034 6025:9035 6065:9035 6026:9033 6066:9033 6026:9034 6066:9034 6026:9035 6066:9035 6027:9033 6067:9033 6027:9034 6067:9034 6027:9035 6067:9035 6028:9033 6068:9033 6028:9034 6068:9034 6028:9035 6068:9035 6029:9033 6069:9033 6029:9034 6069:9034 6029:9035 6069:9035 6030:9033 6070:9033 6030:9034 6070:9034 6030:9035 6070:9035 6031:9033 6071:9033 6031:9034 6071:9034 6031:9035 6071:9035 6032:9033 6072:9033 6032:9034 6072:9034 6032:9035 6072:9035 6033:9033 6073:9033 6033:9034 6073:9034 6033:9035 6073:9035 6034:9033 6074:9033 6034:9034 6074:9034 6034:9035 6074:9035 6035:9033 6075:9033 6035:9034 6075:9034 6035:9035 6075:9035 6036:9033 6076:9033 6036:9034 6076:9034 6036:9035 6076:9035 6037:9033 6077:9033 6037:9034 6077:9034 6037:9035 6077:9035 6038:9033 6078:9033 6038:9034 6078:9034 6038:9035 6078:9035 6039:9033 6039:9034 6039:9035 6000:9036 6040:9036 6000:9037 6040:9037 6000:9038 6040:9038 6001:9036 6041:9036 6001:9037 6041:9037 6001:9038 6041:9038 6002:9036 6042:9036 6002:9037 6042:9037 6002:9038 6042:9038 6003:9036 6043:9036 6003:9037 6043:9037 6003:9038 6043:9038 6004:9036 6044:9036 6004:9037 6044:9037 6004:9038 6044:9038 6005:9036 6045:9036 6005:9037 6045:9037 6005:9038 6045:9038 6006:9036 6046:9036 6006:9037 6046:9037 6006:9038 6046:9038 6007:9036 6047:9036 6007:9037 6047:9037 6007:9038 6047:9038 6008:9036 6048:9036 6008:9037 6048:9037 6008:9038 6048:9038 6009:9036 6049:9036 6009:9037 6049:9037 6009:9038 6049:9038 6010:9036 6050:9036 6010:9037 6050:9037 6010:9038 6050:9038 6011:9036 6051:9036 6011:9037 6051:9037 6011:9038 6051:9038 6012:9036 6052:9036 6012:9037 6052:9037 6012:9038 6052:9038 6013:9036 6053:9036 6013:9037 6053:9037 6013:9038 6053:9038 6014:9036 6054:9036 6014:9037 6054:9037 6014:9038 6054:9038 6015:9036 6055:9036 6015:9037 6055:9037 6015:9038 6055:9038 6016:9036 6056:9036 6016:9037 6056:9037 6016:9038 6056:9038 6017:9036 6057:9036 6017:9037 6057:9037 6017:9038 6057:9038 6018:9036 6058:9036 6018:9037 6058:9037 6018:9038 6058:9038 6019:9036 6059:9036 6019:9037 6059:9037 6019:9038 6059:9038 6020:9036 6060:9036 6020:9037 6060:9037 6020:9038 6060:9038 6021:9036 6061:9036 6021:9037 6061:9037 6021:9038 6061:9038 6022:9036 6062:9036 6022:9037 6062:9037 6022:9038 6062:9038 6023:9036 6063:9036 6023:9037 6063:9037 6023:9038 6063:9038 6024:9036 6064:9036 6024:9037 6064:9037 6024:9038 6064:9038 6025:9036 6065:9036 6025:9037 6065:9037 6025:9038 6065:9038 6026:9036 6066:9036 6026:9037 6066:9037 6026:9038 6066:9038 6027:9036 6067:9036 6027:9037 6067:9037 6027:9038 6067:9038 6028:9036 6068:9036 6028:9037 6068:9037 6028:9038 6068:9038 6029:9036 6069:9036 6029:9037 6069:9037 6029:9038 6069:9038 6030:9036 6070:9036 6030:9037 6070:9037 6030:9038 6070:9038 6031:9036 6071:9036 6031:9037 6071:9037 6031:9038 6071:9038 6032:9036 6072:9036 6032:9037 6072:9037 6032:9038 6072:9038 6033:9036 6073:9036 6033:9037 6073:9037 6033:9038 6073:9038 6034:9036 6074:9036 6034:9037 6074:9037 6034:9038 6074:9038 6035:9036 6075:9036 6035:9037 6075:9037 6035:9038 6075:9038 6036:9036 6076:9036 6036:9037 6076:9037 6036:9038 6076:9038 6037:9036 6077:9036 6037:9037 6077:9037 6037:9038 6077:9038 6038:9036 6078:9036 6038:9037 6078:9037 6038:9038 6078:9038 6039:9036 6039:9037 6039:9038 6000:9039 6040:9039 6000:9040 6040:9040 6000:9041 6040:9041 6001:9039 6041:9039 6001:9040 6041:9040 6001:9041 6041:9041 6002:9039 6042:9039 6002:9040 6042:9040 6002:9041 6042:9041 6003:9039 6043:9039 6003:9040 6043:9040 6003:9041 6043:9041 6004:9039 6044:9039 6004:9040 6044:9040 6004:9041 6044:9041 6005:9039 6045:9039 6005:9040 6045:9040 6005:9041 6045:9041 6006:9039 6046:9039 6006:9040 6046:9040 6006:9041 6046:9041 6007:9039 6047:9039 6007:9040 6047:9040 6007:9041 6047:9041 6008:9039 6048:9039 6008:9040 6048:9040 6008:9041 6048:9041 6009:9039 6049:9039 6009:9040 6049:9040 6009:9041 6049:9041 6010:9039 6050:9039 6010:9040 6050:9040 6010:9041 6050:9041 6011:9039 6051:9039 6011:9040 6051:9040 6011:9041 6051:9041 6012:9039 6052:9039 6012:9040 6052:9040 6012:9041 6052:9041 6013:9039 6053:9039 6013:9040 6053:9040 6013:9041 6053:9041 6014:9039 6054:9039 6014:9040 6054:9040 6014:9041 6054:9041 6015:9039 6055:9039 6015:9040 6055:9040 6015:9041 6055:9041 6016:9039 6056:9039 6016:9040 6056:9040 6016:9041 6056:9041 6017:9039 6057:9039 6017:9040 6057:9040 6017:9041 6057:9041 6018:9039 6058:9039 6018:9040 6058:9040 6018:9041 6058:9041 6019:9039 6059:9039 6019:9040 6059:9040 6019:9041 6059:9041 6020:9039 6060:9039 6020:9040 6060:9040 6020:9041 6060:9041 6021:9039 6061:9039 6021:9040 6061:9040 6021:9041 6061:9041 6022:9039 6062:9039 6022:9040 6062:9040 6022:9041 6062:9041 6023:9039 6063:9039 6023:9040 6063:9040 6023:9041 6063:9041 6024:9039 6064:9039 6024:9040 6064:9040 6024:9041 6064:9041 6025:9039 6065:9039 6025:9040 6065:9040 6025:9041 6065:9041 6026:9039 6066:9039 6026:9040 6066:9040 6026:9041 6066:9041 6027:9039 6067:9039 6027:9040 6067:9040 6027:9041 6067:9041 6028:9039 6068:9039 6028:9040 6068:9040 6028:9041 6068:9041 6029:9039 6069:9039 6029:9040 6069:9040 6029:9041 6069:9041 6030:9039 6070:9039 6030:9040 6070:9040 6030:9041 6070:9041 6031:9039 6071:9039 6031:9040 6071:9040 6031:9041 6071:9041 6032:9039 6072:9039 6032:9040 6072:9040 6032:9041 6072:9041 6033:9039 6073:9039 6033:9040 6073:9040 6033:9041 6073:9041 6034:9039 6074:9039 6034:9040 6074:9040 6034:9041 6074:9041 6035:9039 6075:9039 6035:9040 6075:9040 6035:9041 6075:9041 6036:9039 6076:9039 6036:9040 6076:9040 6036:9041 6076:9041 6037:9039 6077:9039 6037:9040 6077:9040 6037:9041 6077:9041 6038:9039 6078:9039 6038:9040 6078:9040 6038:9041 6078:9041 6039:9039 6039:9040 6039:9041 6000:9042 6040:9042 6000:9043 6040:9043 6000:9044 6040:9044 6001:9042 6041:9042 6001:9043 6041:9043 6001:9044 6041:9044 6002:9042 6042:9042 6002:9043 6042:9043 6002:9044 6042:9044 6003:9042 6043:9042 6003:9043 6043:9043 6003:9044 6043:9044 6004:9042 6044:9042 6004:9043 6044:9043 6004:9044 6044:9044 6005:9042 6045:9042 6005:9043 6045:9043 6005:9044 6045:9044 6006:9042 6046:9042 6006:9043 6046:9043 6006:9044 6046:9044 6007:9042 6047:9042 6007:9043 6047:9043 6007:9044 6047:9044 6008:9042 6048:9042 6008:9043 6048:9043 6008:9044 6048:9044 6009:9042 6049:9042 6009:9043 6049:9043 6009:9044 6049:9044 6010:9042 6050:9042 6010:9043 6050:9043 6010:9044 6050:9044 6011:9042 6051:9042 6011:9043 6051:9043 6011:9044 6051:9044 6012:9042 6052:9042 6012:9043 6052:9043 6012:9044 6052:9044 6013:9042 6053:9042 6013:9043 6053:9043 6013:9044 6053:9044 6014:9042 6054:9042 6014:9043 6054:9043 6014:9044 6054:9044 6015:9042 6055:9042 6015:9043 6055:9043 6015:9044 6055:9044 6016:9042 6056:9042 6016:9043 6056:9043 6016:9044 6056:9044 6017:9042 6057:9042 6017:9043 6057:9043 6017:9044 6057:9044 6018:9042 6058:9042 6018:9043 6058:9043 6018:9044 6058:9044 6019:9042 6059:9042 6019:9043 6059:9043 6019:9044 6059:9044 6020:9042 6060:9042 6020:9043 6060:9043 6020:9044 6060:9044 6021:9042 6061:9042 6021:9043 6061:9043 6021:9044 6061:9044 6022:9042 6062:9042 6022:9043 6062:9043 6022:9044 6062:9044 6023:9042 6063:9042 6023:9043 6063:9043 6023:9044 6063:9044 6024:9042 6064:9042 6024:9043 6064:9043 6024:9044 6064:9044 6025:9042 6065:9042 6025:9043 6065:9043 6025:9044 6065:9044 6026:9042 6066:9042 6026:9043 6066:9043 6026:9044 6066:9044 6027:9042 6067:9042 6027:9043 6067:9043 6027:9044 6067:9044 6028:9042 6068:9042 6028:9043 6068:9043 6028:9044 6068:9044 6029:9042 6069:9042 6029:9043 6069:9043 6029:9044 6069:9044 6030:9042 6070:9042 6030:9043 6070:9043 6030:9044 6070:9044 6031:9042 6071:9042 6031:9043 6071:9043 6031:9044 6071:9044 6032:9042 6072:9042 6032:9043 6072:9043 6032:9044 6072:9044 6033:9042 6073:9042 6033:9043 6073:9043 6033:9044 6073:9044 6034:9042 6074:9042 6034:9043 6074:9043 6034:9044 6074:9044 6035:9042 6075:9042 6035:9043 6075:9043 6035:9044 6075:9044 6036:9042 6076:9042 6036:9043 6076:9043 6036:9044 6076:9044 6037:9042 6077:9042 6037:9043 6077:9043 6037:9044 6077:9044 6038:9042 6078:9042 6038:9043 6078:9043 6038:9044 6078:9044 6039:9042 6039:9043 6039:9044 6000:9045 6040:9045 6000:9046 6040:9046 6000:9047 6040:9047 6001:9045 6041:9045 6001:9046 6041:9046 6001:9047 6041:9047 6002:9045 6042:9045 6002:9046 6042:9046 6002:9047 6042:9047 6003:9045 6043:9045 6003:9046 6043:9046 6003:9047 6043:9047 6004:9045 6044:9045 6004:9046 6044:9046 6004:9047 6044:9047 6005:9045 6045:9045 6005:9046 6045:9046 6005:9047 6045:9047 6006:9045 6046:9045 6006:9046 6046:9046 6006:9047 6046:9047 6007:9045 6047:9045 6007:9046 6047:9046 6007:9047 6047:9047 6008:9045 6048:9045 6008:9046 6048:9046 6008:9047 6048:9047 6009:9045 6049:9045 6009:9046 6049:9046 6009:9047 6049:9047 6010:9045 6050:9045 6010:9046 6050:9046 6010:9047 6050:9047 6011:9045 6051:9045 6011:9046 6051:9046 6011:9047 6051:9047 6012:9045 6052:9045 6012:9046 6052:9046 6012:9047 6052:9047 6013:9045 6053:9045 6013:9046 6053:9046 6013:9047 6053:9047 6014:9045 6054:9045 6014:9046 6054:9046 6014:9047 6054:9047 6015:9045 6055:9045 6015:9046 6055:9046 6015:9047 6055:9047 6016:9045 6056:9045 6016:9046 6056:9046 6016:9047 6056:9047 6017:9045 6057:9045 6017:9046 6057:9046 6017:9047 6057:9047 6018:9045 6058:9045 6018:9046 6058:9046 6018:9047 6058:9047 6019:9045 6059:9045 6019:9046 6059:9046 6019:9047 6059:9047 6020:9045 6060:9045 6020:9046 6060:9046 6020:9047 6060:9047 6021:9045 6061:9045 6021:9046 6061:9046 6021:9047 6061:9047 6022:9045 6062:9045 6022:9046 6062:9046 6022:9047 6062:9047 6023:9045 6063:9045 6023:9046 6063:9046 6023:9047 6063:9047 6024:9045 6064:9045 6024:9046 6064:9046 6024:9047 6064:9047 6025:9045 6065:9045 6025:9046 6065:9046 6025:9047 6065:9047 6026:9045 6066:9045 6026:9046 6066:9046 6026:9047 6066:9047 6027:9045 6067:9045 6027:9046 6067:9046 6027:9047 6067:9047 6028:9045 6068:9045 6028:9046 6068:9046 6028:9047 6068:9047 6029:9045 6069:9045 6029:9046 6069:9046 6029:9047 6069:9047 6030:9045 6070:9045 6030:9046 6070:9046 6030:9047 6070:9047 6031:9045 6071:9045 6031:9046 6071:9046 6031:9047 6071:9047 6032:9045 6072:9045 6032:9046 6072:9046 6032:9047 6072:9047 6033:9045 6073:9045 6033:9046 6073:9046 6033:9047 6073:9047 6034:9045 6074:9045 6034:9046 6074:9046 6034:9047 6074:9047 6035:9045 6075:9045 6035:9046 6075:9046 6035:9047 6075:9047 6036:9045 6076:9045 6036:9046 6076:9046 6036:9047 6076:9047 6037:9045 6077:9045 6037:9046 6077:9046 6037:9047 6077:9047 6038:9045 6078:9045 6038:9046 6078:9046 6038:9047 6078:9047 6039:9045 6039:9046 6039:9047 6000:9048 6040:9048 6000:9049 6040:9049 6000:9050 6040:9050 6001:9048 6041:9048 6001:9049 6041:9049 6001:9050 6041:9050 6002:9048 6042:9048 6002:9049 6042:9049 6002:9050 6042:9050 6003:9048 6043:9048 6003:9049 6043:9049 6003:9050 6043:9050 6004:9048 6044:9048 6004:9049 6044:9049 6004:9050 6044:9050 6005:9048 6045:9048 6005:9049 6045:9049 6005:9050 6045:9050 6006:9048 6046:9048 6006:9049 6046:9049 6006:9050 6046:9050 6007:9048 6047:9048 6007:9049 6047:9049 6007:9050 6047:9050 6008:9048 6048:9048 6008:9049 6048:9049 6008:9050 6048:9050 6009:9048 6049:9048 6009:9049 6049:9049 6009:9050 6049:9050 6010:9048 6050:9048 6010:9049 6050:9049 6010:9050 6050:9050 6011:9048 6051:9048 6011:9049 6051:9049 6011:9050 6051:9050 6012:9048 6052:9048 6012:9049 6052:9049 6012:9050 6052:9050 6013:9048 6053:9048 6013:9049 6053:9049 6013:9050 6053:9050 6014:9048 6054:9048 6014:9049 6054:9049 6014:9050 6054:9050 6015:9048 6055:9048 6015:9049 6055:9049 6015:9050 6055:9050 6016:9048 6056:9048 6016:9049 6056:9049 6016:9050 6056:9050 6017:9048 6057:9048 6017:9049 6057:9049 6017:9050 6057:9050 6018:9048 6058:9048 6018:9049 6058:9049 6018:9050 6058:9050 6019:9048 6059:9048 6019:9049 6059:9049 6019:9050 6059:9050 6020:9048 6060:9048 6020:9049 6060:9049 6020:9050 6060:9050 6021:9048 6061:9048 6021:9049 6061:9049 6021:9050 6061:9050 6022:9048 6062:9048 6022:9049 6062:9049 6022:9050 6062:9050 6023:9048 6063:9048 6023:9049 6063:9049 6023:9050 6063:9050 6024:9048 6064:9048 6024:9049 6064:9049 6024:9050 6064:9050 6025:9048 6065:9048 6025:9049 6065:9049 6025:9050 6065:9050 6026:9048 6066:9048 6026:9049 6066:9049 6026:9050 6066:9050 6027:9048 6067:9048 6027:9049 6067:9049 6027:9050 6067:9050 6028:9048 6068:9048 6028:9049 6068:9049 6028:9050 6068:9050 6029:9048 6069:9048 6029:9049 6069:9049 6029:9050 6069:9050 6030:9048 6070:9048 6030:9049 6070:9049 6030:9050 6070:9050 6031:9048 6071:9048 6031:9049 6071:9049 6031:9050 6071:9050 6032:9048 6072:9048 6032:9049 6072:9049 6032:9050 6072:9050 6033:9048 6073:9048 6033:9049 6073:9049 6033:9050 6073:9050 6034:9048 6074:9048 6034:9049 6074:9049 6034:9050 6074:9050 6035:9048 6075:9048 6035:9049 6075:9049 6035:9050 6075:9050 6036:9048 6076:9048 6036:9049 6076:9049 6036:9050 6076:9050 6037:9048 6077:9048 6037:9049 6077:9049 6037:9050 6077:9050 6038:9048 6078:9048 6038:9049 6078:9049 6038:9050 6078:9050 6039:9048 6039:9049 6039:9050 6000:9051 6040:9051 6000:9052 6040:9052 6000:9053 6040:9053 6001:9051 6041:9051 6001:9052 6041:9052 6001:9053 6041:9053 6002:9051 6042:9051 6002:9052 6042:9052 6002:9053 6042:9053 6003:9051 6043:9051 6003:9052 6043:9052 6003:9053 6043:9053 6004:9051 6044:9051 6004:9052 6044:9052 6004:9053 6044:9053 6005:9051 6045:9051 6005:9052 6045:9052 6005:9053 6045:9053 6006:9051 6046:9051 6006:9052 6046:9052 6006:9053 6046:9053 6007:9051 6047:9051 6007:9052 6047:9052 6007:9053 6047:9053 6008:9051 6048:9051 6008:9052 6048:9052 6008:9053 6048:9053 6009:9051 6049:9051 6009:9052 6049:9052 6009:9053 6049:9053 6010:9051 6050:9051 6010:9052 6050:9052 6010:9053 6050:9053 6011:9051 6051:9051 6011:9052 6051:9052 6011:9053 6051:9053 6012:9051 6052:9051 6012:9052 6052:9052 6012:9053 6052:9053 6013:9051 6053:9051 6013:9052 6053:9052 6013:9053 6053:9053 6014:9051 6054:9051 6014:9052 6054:9052 6014:9053 6054:9053 6015:9051 6055:9051 6015:9052 6055:9052 6015:9053 6055:9053 6016:9051 6056:9051 6016:9052 6056:9052 6016:9053 6056:9053 6017:9051 6057:9051 6017:9052 6057:9052 6017:9053 6057:9053 6018:9051 6058:9051 6018:9052 6058:9052 6018:9053 6058:9053 6019:9051 6059:9051 6019:9052 6059:9052 6019:9053 6059:9053 6020:9051 6060:9051 6020:9052 6060:9052 6020:9053 6060:9053 6021:9051 6061:9051 6021:9052 6061:9052 6021:9053 6061:9053 6022:9051 6062:9051 6022:9052 6062:9052 6022:9053 6062:9053 6023:9051 6063:9051 6023:9052 6063:9052 6023:9053 6063:9053 6024:9051 6064:9051 6024:9052 6064:9052 6024:9053 6064:9053 6025:9051 6065:9051 6025:9052 6065:9052 6025:9053 6065:9053 6026:9051 6066:9051 6026:9052 6066:9052 6026:9053 6066:9053 6027:9051 6067:9051 6027:9052 6067:9052 6027:9053 6067:9053 6028:9051 6068:9051 6028:9052 6068:9052 6028:9053 6068:9053 6029:9051 6069:9051 6029:9052 6069:9052 6029:9053 6069:9053 6030:9051 6070:9051 6030:9052 6070:9052 6030:9053 6070:9053 6031:9051 6071:9051 6031:9052 6071:9052 6031:9053 6071:9053 6032:9051 6072:9051 6032:9052 6072:9052 6032:9053 6072:9053 6033:9051 6073:9051 6033:9052 6073:9052 6033:9053 6073:9053 6034:9051 6074:9051 6034:9052 6074:9052 6034:9053 6074:9053 6035:9051 6075:9051 6035:9052 6075:9052 6035:9053 6075:9053 6036:9051 6076:9051 6036:9052 6076:9052 6036:9053 6076:9053 6037:9051 6077:9051 6037:9052 6077:9052 6037:9053 6077:9053 6038:9051 6078:9051 6038:9052 6078:9052 6038:9053 6078:9053 6039:9051 6039:9052 6039:9053 6000:9054 6040:9054 6000:9055 6040:9055 6000:9056 6040:9056 6001:9054 6041:9054 6001:9055 6041:9055 6001:9056 6041:9056 6002:9054 6042:9054 6002:9055 6042:9055 6002:9056 6042:9056 6003:9054 6043:9054 6003:9055 6043:9055 6003:9056 6043:9056 6004:9054 6044:9054 6004:9055 6044:9055 6004:9056 6044:9056 6005:9054 6045:9054 6005:9055 6045:9055 6005:9056 6045:9056 6006:9054 6046:9054 6006:9055 6046:9055 6006:9056 6046:9056 6007:9054 6047:9054 6007:9055 6047:9055 6007:9056 6047:9056 6008:9054 6048:9054 6008:9055 6048:9055 6008:9056 6048:9056 6009:9054 6049:9054 6009:9055 6049:9055 6009:9056 6049:9056 6010:9054 6050:9054 6010:9055 6050:9055 6010:9056 6050:9056 6011:9054 6051:9054 6011:9055 6051:9055 6011:9056 6051:9056 6012:9054 6052:9054 6012:9055 6052:9055 6012:9056 6052:9056 6013:9054 6053:9054 6013:9055 6053:9055 6013:9056 6053:9056 6014:9054 6054:9054 6014:9055 6054:9055 6014:9056 6054:9056 6015:9054 6055:9054 6015:9055 6055:9055 6015:9056 6055:9056 6016:9054 6056:9054 6016:9055 6056:9055 6016:9056 6056:9056 6017:9054 6057:9054 6017:9055 6057:9055 6017:9056 6057:9056 6018:9054 6058:9054 6018:9055 6058:9055 6018:9056 6058:9056 6019:9054 6059:9054 6019:9055 6059:9055 6019:9056 6059:9056 6020:9054 6060:9054 6020:9055 6060:9055 6020:9056 6060:9056 6021:9054 6061:9054 6021:9055 6061:9055 6021:9056 6061:9056 6022:9054 6062:9054 6022:9055 6062:9055 6022:9056 6062:9056 6023:9054 6063:9054 6023:9055 6063:9055 6023:9056 6063:9056 6024:9054 6064:9054 6024:9055 6064:9055 6024:9056 6064:9056 6025:9054 6065:9054 6025:9055 6065:9055 6025:9056 6065:9056 6026:9054 6066:9054 6026:9055 6066:9055 6026:9056 6066:9056 6027:9054 6067:9054 6027:9055 6067:9055 6027:9056 6067:9056 6028:9054 6068:9054 6028:9055 6068:9055 6028:9056 6068:9056 6029:9054 6069:9054 6029:9055 6069:9055 6029:9056 6069:9056 6030:9054 6070:9054 6030:9055 6070:9055 6030:9056 6070:9056 6031:9054 6071:9054 6031:9055 6071:9055 6031:9056 6071:9056 6032:9054 6072:9054 6032:9055 6072:9055 6032:9056 6072:9056 6033:9054 6073:9054 6033:9055 6073:9055 6033:9056 6073:9056 6034:9054 6074:9054 6034:9055 6074:9055 6034:9056 6074:9056 6035:9054 6075:9054 6035:9055 6075:9055 6035:9056 6075:9056 6036:9054 6076:9054 6036:9055 6076:9055 6036:9056 6076:9056 6037:9054 6077:9054 6037:9055 6077:9055 6037:9056 6077:9056 6038:9054 6078:9054 6038:9055 6078:9055 6038:9056 6078:9056 6039:9054 6039:9055 6039:9056 6000:9057 6040:9057 6000:9058 6040:9058 6000:9059 6040:9059 6001:9057 6041:9057 6001:9058 6041:9058 6001:9059 6041:9059 6002:9057 6042:9057 6002:9058 6042:9058 6002:9059 6042:9059 6003:9057 6043:9057 6003:9058 6043:9058 6003:9059 6043:9059 6004:9057 6044:9057 6004:9058 6044:9058 6004:9059 6044:9059 6005:9057 6045:9057 6005:9058 6045:9058 6005:9059 6045:9059 6006:9057 6046:9057 6006:9058 6046:9058 6006:9059 6046:9059 6007:9057 6047:9057 6007:9058 6047:9058 6007:9059 6047:9059 6008:9057 6048:9057 6008:9058 6048:9058 6008:9059 6048:9059 6009:9057 6049:9057 6009:9058 6049:9058 6009:9059 6049:9059 6010:9057 6050:9057 6010:9058 6050:9058 6010:9059 6050:9059 6011:9057 6051:9057 6011:9058 6051:9058 6011:9059 6051:9059 6012:9057 6052:9057 6012:9058 6052:9058 6012:9059 6052:9059 6013:9057 6053:9057 6013:9058 6053:9058 6013:9059 6053:9059 6014:9057 6054:9057 6014:9058 6054:9058 6014:9059 6054:9059 6015:9057 6055:9057 6015:9058 6055:9058 6015:9059 6055:9059 6016:9057 6056:9057 6016:9058 6056:9058 6016:9059 6056:9059 6017:9057 6057:9057 6017:9058 6057:9058 6017:9059 6057:9059 6018:9057 6058:9057 6018:9058 6058:9058 6018:9059 6058:9059 6019:9057 6059:9057 6019:9058 6059:9058 6019:9059 6059:9059 6020:9057 6060:9057 6020:9058 6060:9058 6020:9059 6060:9059 6021:9057 6061:9057 6021:9058 6061:9058 6021:9059 6061:9059 6022:9057 6062:9057 6022:9058 6062:9058 6022:9059 6062:9059 6023:9057 6063:9057 6023:9058 6063:9058 6023:9059 6063:9059 6024:9057 6064:9057 6024:9058 6064:9058 6024:9059 6064:9059 6025:9057 6065:9057 6025:9058 6065:9058 6025:9059 6065:9059 6026:9057 6066:9057 6026:9058 6066:9058 6026:9059 6066:9059 6027:9057 6067:9057 6027:9058 6067:9058 6027:9059 6067:9059 6028:9057 6068:9057 6028:9058 6068:9058 6028:9059 6068:9059 6029:9057 6069:9057 6029:9058 6069:9058 6029:9059 6069:9059 6030:9057 6070:9057 6030:9058 6070:9058 6030:9059 6070:9059 6031:9057 6071:9057 6031:9058 6071:9058 6031:9059 6071:9059 6032:9057 6072:9057 6032:9058 6072:9058 6032:9059 6072:9059 6033:9057 6073:9057 6033:9058 6073:9058 6033:9059 6073:9059 6034:9057 6074:9057 6034:9058 6074:9058 6034:9059 6074:9059 6035:9057 6075:9057 6035:9058 6075:9058 6035:9059 6075:9059 6036:9057 6076:9057 6036:9058 6076:9058 6036:9059 6076:9059 6037:9057 6077:9057 6037:9058 6077:9058 6037:9059 6077:9059 6038:9057 6078:9057 6038:9058 6078:9058 6038:9059 6078:9059 6039:9057 6039:9058 6039:9059 6000:9060 6040:9060 6000:9061 6040:9061 6000:9062 6040:9062 6001:9060 6041:9060 6001:9061 6041:9061 6001:9062 6041:9062 6002:9060 6042:9060 6002:9061 6042:9061 6002:9062 6042:9062 6003:9060 6043:9060 6003:9061 6043:9061 6003:9062 6043:9062 6004:9060 6044:9060 6004:9061 6044:9061 6004:9062 6044:9062 6005:9060 6045:9060 6005:9061 6045:9061 6005:9062 6045:9062 6006:9060 6046:9060 6006:9061 6046:9061 6006:9062 6046:9062 6007:9060 6047:9060 6007:9061 6047:9061 6007:9062 6047:9062 6008:9060 6048:9060 6008:9061 6048:9061 6008:9062 6048:9062 6009:9060 6049:9060 6009:9061 6049:9061 6009:9062 6049:9062 6010:9060 6050:9060 6010:9061 6050:9061 6010:9062 6050:9062 6011:9060 6051:9060 6011:9061 6051:9061 6011:9062 6051:9062 6012:9060 6052:9060 6012:9061 6052:9061 6012:9062 6052:9062 6013:9060 6053:9060 6013:9061 6053:9061 6013:9062 6053:9062 6014:9060 6054:9060 6014:9061 6054:9061 6014:9062 6054:9062 6015:9060 6055:9060 6015:9061 6055:9061 6015:9062 6055:9062 6016:9060 6056:9060 6016:9061 6056:9061 6016:9062 6056:9062 6017:9060 6057:9060 6017:9061 6057:9061 6017:9062 6057:9062 6018:9060 6058:9060 6018:9061 6058:9061 6018:9062 6058:9062 6019:9060 6059:9060 6019:9061 6059:9061 6019:9062 6059:9062 6020:9060 6060:9060 6020:9061 6060:9061 6020:9062 6060:9062 6021:9060 6061:9060 6021:9061 6061:9061 6021:9062 6061:9062 6022:9060 6062:9060 6022:9061 6062:9061 6022:9062 6062:9062 6023:9060 6063:9060 6023:9061 6063:9061 6023:9062 6063:9062 6024:9060 6064:9060 6024:9061 6064:9061 6024:9062 6064:9062 6025:9060 6065:9060 6025:9061 6065:9061 6025:9062 6065:9062 6026:9060 6066:9060 6026:9061 6066:9061 6026:9062 6066:9062 6027:9060 6067:9060 6027:9061 6067:9061 6027:9062 6067:9062 6028:9060 6068:9060 6028:9061 6068:9061 6028:9062 6068:9062 6029:9060 6069:9060 6029:9061 6069:9061 6029:9062 6069:9062 6030:9060 6070:9060 6030:9061 6070:9061 6030:9062 6070:9062 6031:9060 6071:9060 6031:9061 6071:9061 6031:9062 6071:9062 6032:9060 6072:9060 6032:9061 6072:9061 6032:9062 6072:9062 6033:9060 6073:9060 6033:9061 6073:9061 6033:9062 6073:9062 6034:9060 6074:9060 6034:9061 6074:9061 6034:9062 6074:9062 6035:9060 6075:9060 6035:9061 6075:9061 6035:9062 6075:9062 6036:9060 6076:9060 6036:9061 6076:9061 6036:9062 6076:9062 6037:9060 6077:9060 6037:9061 6077:9061 6037:9062 6077:9062 6038:9060 6078:9060 6038:9061 6078:9061 6038:9062 6078:9062 6039:9060 6039:9061 6039:9062 6000:9063 6040:9063 6000:9064 6040:9064 6000:9065 6040:9065 6001:9063 6041:9063 6001:9064 6041:9064 6001:9065 6041:9065 6002:9063 6042:9063 6002:9064 6042:9064 6002:9065 6042:9065 6003:9063 6043:9063 6003:9064 6043:9064 6003:9065 6043:9065 6004:9063 6044:9063 6004:9064 6044:9064 6004:9065 6044:9065 6005:9063 6045:9063 6005:9064 6045:9064 6005:9065 6045:9065 6006:9063 6046:9063 6006:9064 6046:9064 6006:9065 6046:9065 6007:9063 6047:9063 6007:9064 6047:9064 6007:9065 6047:9065 6008:9063 6048:9063 6008:9064 6048:9064 6008:9065 6048:9065 6009:9063 6049:9063 6009:9064 6049:9064 6009:9065 6049:9065 6010:9063 6050:9063 6010:9064 6050:9064 6010:9065 6050:9065 6011:9063 6051:9063 6011:9064 6051:9064 6011:9065 6051:9065 6012:9063 6052:9063 6012:9064 6052:9064 6012:9065 6052:9065 6013:9063 6053:9063 6013:9064 6053:9064 6013:9065 6053:9065 6014:9063 6054:9063 6014:9064 6054:9064 6014:9065 6054:9065 6015:9063 6055:9063 6015:9064 6055:9064 6015:9065 6055:9065 6016:9063 6056:9063 6016:9064 6056:9064 6016:9065 6056:9065 6017:9063 6057:9063 6017:9064 6057:9064 6017:9065 6057:9065 6018:9063 6058:9063 6018:9064 6058:9064 6018:9065 6058:9065 6019:9063 6059:9063 6019:9064 6059:9064 6019:9065 6059:9065 6020:9063 6060:9063 6020:9064 6060:9064 6020:9065 6060:9065 6021:9063 6061:9063 6021:9064 6061:9064 6021:9065 6061:9065 6022:9063 6062:9063 6022:9064 6062:9064 6022:9065 6062:9065 6023:9063 6063:9063 6023:9064 6063:9064 6023:9065 6063:9065 6024:9063 6064:9063 6024:9064 6064:9064 6024:9065 6064:9065 6025:9063 6065:9063 6025:9064 6065:9064 6025:9065 6065:9065 6026:9063 6066:9063 6026:9064 6066:9064 6026:9065 6066:9065 6027:9063 6067:9063 6027:9064 6067:9064 6027:9065 6067:9065 6028:9063 6068:9063 6028:9064 6068:9064 6028:9065 6068:9065 6029:9063 6069:9063 6029:9064 6069:9064 6029:9065 6069:9065 6030:9063 6070:9063 6030:9064 6070:9064 6030:9065 6070:9065 6031:9063 6071:9063 6031:9064 6071:9064 6031:9065 6071:9065 6032:9063 6072:9063 6032:9064 6072:9064 6032:9065 6072:9065 6033:9063 6073:9063 6033:9064 6073:9064 6033:9065 6073:9065 6034:9063 6074:9063 6034:9064 6074:9064 6034:9065 6074:9065 6035:9063 6075:9063 6035:9064 6075:9064 6035:9065 6075:9065 6036:9063 6076:9063 6036:9064 6076:9064 6036:9065 6076:9065 6037:9063 6077:9063 6037:9064 6077:9064 6037:9065 6077:9065 6038:9063 6078:9063 6038:9064 6078:9064 6038:9065 6078:9065 6039:9063 6039:9064 6039:9065 6000:9066 6040:9066 6000:9067 6040:9067 6000:9068 6040:9068 6001:9066 6041:9066 6001:9067 6041:9067 6001:9068 6041:9068 6002:9066 6042:9066 6002:9067 6042:9067 6002:9068 6042:9068 6003:9066 6043:9066 6003:9067 6043:9067 6003:9068 6043:9068 6004:9066 6044:9066 6004:9067 6044:9067 6004:9068 6044:9068 6005:9066 6045:9066 6005:9067 6045:9067 6005:9068 6045:9068 6006:9066 6046:9066 6006:9067 6046:9067 6006:9068 6046:9068 6007:9066 6047:9066 6007:9067 6047:9067 6007:9068 6047:9068 6008:9066 6048:9066 6008:9067 6048:9067 6008:9068 6048:9068 6009:9066 6049:9066 6009:9067 6049:9067 6009:9068 6049:9068 6010:9066 6050:9066 6010:9067 6050:9067 6010:9068 6050:9068 6011:9066 6051:9066 6011:9067 6051:9067 6011:9068 6051:9068 6012:9066 6052:9066 6012:9067 6052:9067 6012:9068 6052:9068 6013:9066 6053:9066 6013:9067 6053:9067 6013:9068 6053:9068 6014:9066 6054:9066 6014:9067 6054:9067 6014:9068 6054:9068 6015:9066 6055:9066 6015:9067 6055:9067 6015:9068 6055:9068 6016:9066 6056:9066 6016:9067 6056:9067 6016:9068 6056:9068 6017:9066 6057:9066 6017:9067 6057:9067 6017:9068 6057:9068 6018:9066 6058:9066 6018:9067 6058:9067 6018:9068 6058:9068 6019:9066 6059:9066 6019:9067 6059:9067 6019:9068 6059:9068 6020:9066 6060:9066 6020:9067 6060:9067 6020:9068 6060:9068 6021:9066 6061:9066 6021:9067 6061:9067 6021:9068 6061:9068 6022:9066 6062:9066 6022:9067 6062:9067 6022:9068 6062:9068 6023:9066 6063:9066 6023:9067 6063:9067 6023:9068 6063:9068 6024:9066 6064:9066 6024:9067 6064:9067 6024:9068 6064:9068 6025:9066 6065:9066 6025:9067 6065:9067 6025:9068 6065:9068 6026:9066 6066:9066 6026:9067 6066:9067 6026:9068 6066:9068 6027:9066 6067:9066 6027:9067 6067:9067 6027:9068 6067:9068 6028:9066 6068:9066 6028:9067 6068:9067 6028:9068 6068:9068 6029:9066 6069:9066 6029:9067 6069:9067 6029:9068 6069:9068 6030:9066 6070:9066 6030:9067 6070:9067 6030:9068 6070:9068 6031:9066 6071:9066 6031:9067 6071:9067 6031:9068 6071:9068 6032:9066 6072:9066 6032:9067 6072:9067 6032:9068 6072:9068 6033:9066 6073:9066 6033:9067 6073:9067 6033:9068 6073:9068 6034:9066 6074:9066 6034:9067 6074:9067 6034:9068 6074:9068 6035:9066 6075:9066 6035:9067 6075:9067 6035:9068 6075:9068 6036:9066 6076:9066 6036:9067 6076:9067 6036:9068 6076:9068 6037:9066 6077:9066 6037:9067 6077:9067 6037:9068 6077:9068 6038:9066 6078:9066 6038:9067 6078:9067 6038:9068 6078:9068 6039:9066 6039:9067 6039:9068 6000:9069 6040:9069 6000:9070 6040:9070 6000:9071 6040:9071 6001:9069 6041:9069 6001:9070 6041:9070 6001:9071 6041:9071 6002:9069 6042:9069 6002:9070 6042:9070 6002:9071 6042:9071 6003:9069 6043:9069 6003:9070 6043:9070 6003:9071 6043:9071 6004:9069 6044:9069 6004:9070 6044:9070 6004:9071 6044:9071 6005:9069 6045:9069 6005:9070 6045:9070 6005:9071 6045:9071 6006:9069 6046:9069 6006:9070 6046:9070 6006:9071 6046:9071 6007:9069 6047:9069 6007:9070 6047:9070 6007:9071 6047:9071 6008:9069 6048:9069 6008:9070 6048:9070 6008:9071 6048:9071 6009:9069 6049:9069 6009:9070 6049:9070 6009:9071 6049:9071 6010:9069 6050:9069 6010:9070 6050:9070 6010:9071 6050:9071 6011:9069 6051:9069 6011:9070 6051:9070 6011:9071 6051:9071 6012:9069 6052:9069 6012:9070 6052:9070 6012:9071 6052:9071 6013:9069 6053:9069 6013:9070 6053:9070 6013:9071 6053:9071 6014:9069 6054:9069 6014:9070 6054:9070 6014:9071 6054:9071 6015:9069 6055:9069 6015:9070 6055:9070 6015:9071 6055:9071 6016:9069 6056:9069 6016:9070 6056:9070 6016:9071 6056:9071 6017:9069 6057:9069 6017:9070 6057:9070 6017:9071 6057:9071 6018:9069 6058:9069 6018:9070 6058:9070 6018:9071 6058:9071 6019:9069 6059:9069 6019:9070 6059:9070 6019:9071 6059:9071 6020:9069 6060:9069 6020:9070 6060:9070 6020:9071 6060:9071 6021:9069 6061:9069 6021:9070 6061:9070 6021:9071 6061:9071 6022:9069 6062:9069 6022:9070 6062:9070 6022:9071 6062:9071 6023:9069 6063:9069 6023:9070 6063:9070 6023:9071 6063:9071 6024:9069 6064:9069 6024:9070 6064:9070 6024:9071 6064:9071 6025:9069 6065:9069 6025:9070 6065:9070 6025:9071 6065:9071 6026:9069 6066:9069 6026:9070 6066:9070 6026:9071 6066:9071 6027:9069 6067:9069 6027:9070 6067:9070 6027:9071 6067:9071 6028:9069 6068:9069 6028:9070 6068:9070 6028:9071 6068:9071 6029:9069 6069:9069 6029:9070 6069:9070 6029:9071 6069:9071 6030:9069 6070:9069 6030:9070 6070:9070 6030:9071 6070:9071 6031:9069 6071:9069 6031:9070 6071:9070 6031:9071 6071:9071 6032:9069 6072:9069 6032:9070 6072:9070 6032:9071 6072:9071 6033:9069 6073:9069 6033:9070 6073:9070 6033:9071 6073:9071 6034:9069 6074:9069 6034:9070 6074:9070 6034:9071 6074:9071 6035:9069 6075:9069 6035:9070 6075:9070 6035:9071 6075:9071 6036:9069 6076:9069 6036:9070 6076:9070 6036:9071 6076:9071 6037:9069 6077:9069 6037:9070 6077:9070 6037:9071 6077:9071 6038:9069 6078:9069 6038:9070 6078:9070 6038:9071 6078:9071 6039:9069 6039:9070 6039:9071 6000:9072 6040:9072 6000:9073 6040:9073 6000:9074 6040:9074 6001:9072 6041:9072 6001:9073 6041:9073 6001:9074 6041:9074 6002:9072 6042:9072 6002:9073 6042:9073 6002:9074 6042:9074 6003:9072 6043:9072 6003:9073 6043:9073 6003:9074 6043:9074 6004:9072 6044:9072 6004:9073 6044:9073 6004:9074 6044:9074 6005:9072 6045:9072 6005:9073 6045:9073 6005:9074 6045:9074 6006:9072 6046:9072 6006:9073 6046:9073 6006:9074 6046:9074 6007:9072 6047:9072 6007:9073 6047:9073 6007:9074 6047:9074 6008:9072 6048:9072 6008:9073 6048:9073 6008:9074 6048:9074 6009:9072 6049:9072 6009:9073 6049:9073 6009:9074 6049:9074 6010:9072 6050:9072 6010:9073 6050:9073 6010:9074 6050:9074 6011:9072 6051:9072 6011:9073 6051:9073 6011:9074 6051:9074 6012:9072 6052:9072 6012:9073 6052:9073 6012:9074 6052:9074 6013:9072 6053:9072 6013:9073 6053:9073 6013:9074 6053:9074 6014:9072 6054:9072 6014:9073 6054:9073 6014:9074 6054:9074 6015:9072 6055:9072 6015:9073 6055:9073 6015:9074 6055:9074 6016:9072 6056:9072 6016:9073 6056:9073 6016:9074 6056:9074 6017:9072 6057:9072 6017:9073 6057:9073 6017:9074 6057:9074 6018:9072 6058:9072 6018:9073 6058:9073 6018:9074 6058:9074 6019:9072 6059:9072 6019:9073 6059:9073 6019:9074 6059:9074 6020:9072 6060:9072 6020:9073 6060:9073 6020:9074 6060:9074 6021:9072 6061:9072 6021:9073 6061:9073 6021:9074 6061:9074 6022:9072 6062:9072 6022:9073 6062:9073 6022:9074 6062:9074 6023:9072 6063:9072 6023:9073 6063:9073 6023:9074 6063:9074 6024:9072 6064:9072 6024:9073 6064:9073 6024:9074 6064:9074 6025:9072 6065:9072 6025:9073 6065:9073 6025:9074 6065:9074 6026:9072 6066:9072 6026:9073 6066:9073 6026:9074 6066:9074 6027:9072 6067:9072 6027:9073 6067:9073 6027:9074 6067:9074 6028:9072 6068:9072 6028:9073 6068:9073 6028:9074 6068:9074 6029:9072 6069:9072 6029:9073 6069:9073 6029:9074 6069:9074 6030:9072 6070:9072 6030:9073 6070:9073 6030:9074 6070:9074 6031:9072 6071:9072 6031:9073 6071:9073 6031:9074 6071:9074 6032:9072 6072:9072 6032:9073 6072:9073 6032:9074 6072:9074 6033:9072 6073:9072 6033:9073 6073:9073 6033:9074 6073:9074 6034:9072 6074:9072 6034:9073 6074:9073 6034:9074 6074:9074 6035:9072 6075:9072 6035:9073 6075:9073 6035:9074 6075:9074 6036:9072 6076:9072 6036:9073 6076:9073 6036:9074 6076:9074 6037:9072 6077:9072 6037:9073 6077:9073 6037:9074 6077:9074 6038:9072 6078:9072 6038:9073 6078:9073 6038:9074 6078:9074 6039:9072 6039:9073 6039:9074 6000:9075 6040:9075 6000:9076 6040:9076 6000:9077 6040:9077 6001:9075 6041:9075 6001:9076 6041:9076 6001:9077 6041:9077 6002:9075 6042:9075 6002:9076 6042:9076 6002:9077 6042:9077 6003:9075 6043:9075 6003:9076 6043:9076 6003:9077 6043:9077 6004:9075 6044:9075 6004:9076 6044:9076 6004:9077 6044:9077 6005:9075 6045:9075 6005:9076 6045:9076 6005:9077 6045:9077 6006:9075 6046:9075 6006:9076 6046:9076 6006:9077 6046:9077 6007:9075 6047:9075 6007:9076 6047:9076 6007:9077 6047:9077 6008:9075 6048:9075 6008:9076 6048:9076 6008:9077 6048:9077 6009:9075 6049:9075 6009:9076 6049:9076 6009:9077 6049:9077 6010:9075 6050:9075 6010:9076 6050:9076 6010:9077 6050:9077 6011:9075 6051:9075 6011:9076 6051:9076 6011:9077 6051:9077 6012:9075 6052:9075 6012:9076 6052:9076 6012:9077 6052:9077 6013:9075 6053:9075 6013:9076 6053:9076 6013:9077 6053:9077 6014:9075 6054:9075 6014:9076 6054:9076 6014:9077 6054:9077 6015:9075 6055:9075 6015:9076 6055:9076 6015:9077 6055:9077 6016:9075 6056:9075 6016:9076 6056:9076 6016:9077 6056:9077 6017:9075 6057:9075 6017:9076 6057:9076 6017:9077 6057:9077 6018:9075 6058:9075 6018:9076 6058:9076 6018:9077 6058:9077 6019:9075 6059:9075 6019:9076 6059:9076 6019:9077 6059:9077 6020:9075 6060:9075 6020:9076 6060:9076 6020:9077 6060:9077 6021:9075 6061:9075 6021:9076 6061:9076 6021:9077 6061:9077 6022:9075 6062:9075 6022:9076 6062:9076 6022:9077 6062:9077 6023:9075 6063:9075 6023:9076 6063:9076 6023:9077 6063:9077 6024:9075 6064:9075 6024:9076 6064:9076 6024:9077 6064:9077 6025:9075 6065:9075 6025:9076 6065:9076 6025:9077 6065:9077 6026:9075 6066:9075 6026:9076 6066:9076 6026:9077 6066:9077 6027:9075 6067:9075 6027:9076 6067:9076 6027:9077 6067:9077 6028:9075 6068:9075 6028:9076 6068:9076 6028:9077 6068:9077 6029:9075 6069:9075 6029:9076 6069:9076 6029:9077 6069:9077 6030:9075 6070:9075 6030:9076 6070:9076 6030:9077 6070:9077 6031:9075 6071:9075 6031:9076 6071:9076 6031:9077 6071:9077 6032:9075 6072:9075 6032:9076 6072:9076 6032:9077 6072:9077 6033:9075 6073:9075 6033:9076 6073:9076 6033:9077 6073:9077 6034:9075 6074:9075 6034:9076 6074:9076 6034:9077 6074:9077 6035:9075 6075:9075 6035:9076 6075:9076 6035:9077 6075:9077 6036:9075 6076:9075 6036:9076 6076:9076 6036:9077 6076:9077 6037:9075 6077:9075 6037:9076 6077:9076 6037:9077 6077:9077 6038:9075 6078:9075 6038:9076 6078:9076 6038:9077 6078:9077 6039:9075 6039:9076 6039:9077 6000:9078 6040:9078 6000:9079 6040:9079 6000:9080 6040:9080 6001:9078 6041:9078 6001:9079 6041:9079 6001:9080 6041:9080 6002:9078 6042:9078 6002:9079 6042:9079 6002:9080 6042:9080 6003:9078 6043:9078 6003:9079 6043:9079 6003:9080 6043:9080 6004:9078 6044:9078 6004:9079 6044:9079 6004:9080 6044:9080 6005:9078 6045:9078 6005:9079 6045:9079 6005:9080 6045:9080 6006:9078 6046:9078 6006:9079 6046:9079 6006:9080 6046:9080 6007:9078 6047:9078 6007:9079 6047:9079 6007:9080 6047:9080 6008:9078 6048:9078 6008:9079 6048:9079 6008:9080 6048:9080 6009:9078 6049:9078 6009:9079 6049:9079 6009:9080 6049:9080 6010:9078 6050:9078 6010:9079 6050:9079 6010:9080 6050:9080 6011:9078 6051:9078 6011:9079 6051:9079 6011:9080 6051:9080 6012:9078 6052:9078 6012:9079 6052:9079 6012:9080 6052:9080 6013:9078 6053:9078 6013:9079 6053:9079 6013:9080 6053:9080 6014:9078 6054:9078 6014:9079 6054:9079 6014:9080 6054:9080 6015:9078 6055:9078 6015:9079 6055:9079 6015:9080 6055:9080 6016:9078 6056:9078 6016:9079 6056:9079 6016:9080 6056:9080 6017:9078 6057:9078 6017:9079 6057:9079 6017:9080 6057:9080 6018:9078 6058:9078 6018:9079 6058:9079 6018:9080 6058:9080 6019:9078 6059:9078 6019:9079 6059:9079 6019:9080 6059:9080 6020:9078 6060:9078 6020:9079 6060:9079 6020:9080 6060:9080 6021:9078 6061:9078 6021:9079 6061:9079 6021:9080 6061:9080 6022:9078 6062:9078 6022:9079 6062:9079 6022:9080 6062:9080 6023:9078 6063:9078 6023:9079 6063:9079 6023:9080 6063:9080 6024:9078 6064:9078 6024:9079 6064:9079 6024:9080 6064:9080 6025:9078 6065:9078 6025:9079 6065:9079 6025:9080 6065:9080 6026:9078 6066:9078 6026:9079 6066:9079 6026:9080 6066:9080 6027:9078 6067:9078 6027:9079 6067:9079 6027:9080 6067:9080 6028:9078 6068:9078 6028:9079 6068:9079 6028:9080 6068:9080 6029:9078 6069:9078 6029:9079 6069:9079 6029:9080 6069:9080 6030:9078 6070:9078 6030:9079 6070:9079 6030:9080 6070:9080 6031:9078 6071:9078 6031:9079 6071:9079 6031:9080 6071:9080 6032:9078 6072:9078 6032:9079 6072:9079 6032:9080 6072:9080 6033:9078 6073:9078 6033:9079 6073:9079 6033:9080 6073:9080 6034:9078 6074:9078 6034:9079 6074:9079 6034:9080 6074:9080 6035:9078 6075:9078 6035:9079 6075:9079 6035:9080 6075:9080 6036:9078 6076:9078 6036:9079 6076:9079 6036:9080 6076:9080 6037:9078 6077:9078 6037:9079 6077:9079 6037:9080 6077:9080 6038:9078 6078:9078 6038:9079 6078:9079 6038:9080 6078:9080 6039:9078 6039:9079 6039:9080 6000:9081 6040:9081 6000:9082 6040:9082 6000:9083 6040:9083 6001:9081 6041:9081 6001:9082 6041:9082 6001:9083 6041:9083 6002:9081 6042:9081 6002:9082 6042:9082 6002:9083 6042:9083 6003:9081 6043:9081 6003:9082 6043:9082 6003:9083 6043:9083 6004:9081 6044:9081 6004:9082 6044:9082 6004:9083 6044:9083 6005:9081 6045:9081 6005:9082 6045:9082 6005:9083 6045:9083 6006:9081 6046:9081 6006:9082 6046:9082 6006:9083 6046:9083 6007:9081 6047:9081 6007:9082 6047:9082 6007:9083 6047:9083 6008:9081 6048:9081 6008:9082 6048:9082 6008:9083 6048:9083 6009:9081 6049:9081 6009:9082 6049:9082 6009:9083 6049:9083 6010:9081 6050:9081 6010:9082 6050:9082 6010:9083 6050:9083 6011:9081 6051:9081 6011:9082 6051:9082 6011:9083 6051:9083 6012:9081 6052:9081 6012:9082 6052:9082 6012:9083 6052:9083 6013:9081 6053:9081 6013:9082 6053:9082 6013:9083 6053:9083 6014:9081 6054:9081 6014:9082 6054:9082 6014:9083 6054:9083 6015:9081 6055:9081 6015:9082 6055:9082 6015:9083 6055:9083 6016:9081 6056:9081 6016:9082 6056:9082 6016:9083 6056:9083 6017:9081 6057:9081 6017:9082 6057:9082 6017:9083 6057:9083 6018:9081 6058:9081 6018:9082 6058:9082 6018:9083 6058:9083 6019:9081 6059:9081 6019:9082 6059:9082 6019:9083 6059:9083 6020:9081 6060:9081 6020:9082 6060:9082 6020:9083 6060:9083 6021:9081 6061:9081 6021:9082 6061:9082 6021:9083 6061:9083 6022:9081 6062:9081 6022:9082 6062:9082 6022:9083 6062:9083 6023:9081 6063:9081 6023:9082 6063:9082 6023:9083 6063:9083 6024:9081 6064:9081 6024:9082 6064:9082 6024:9083 6064:9083 6025:9081 6065:9081 6025:9082 6065:9082 6025:9083 6065:9083 6026:9081 6066:9081 6026:9082 6066:9082 6026:9083 6066:9083 6027:9081 6067:9081 6027:9082 6067:9082 6027:9083 6067:9083 6028:9081 6068:9081 6028:9082 6068:9082 6028:9083 6068:9083 6029:9081 6069:9081 6029:9082 6069:9082 6029:9083 6069:9083 6030:9081 6070:9081 6030:9082 6070:9082 6030:9083 6070:9083 6031:9081 6071:9081 6031:9082 6071:9082 6031:9083 6071:9083 6032:9081 6072:9081 6032:9082 6072:9082 6032:9083 6072:9083 6033:9081 6073:9081 6033:9082 6073:9082 6033:9083 6073:9083 6034:9081 6074:9081 6034:9082 6074:9082 6034:9083 6074:9083 6035:9081 6075:9081 6035:9082 6075:9082 6035:9083 6075:9083 6036:9081 6076:9081 6036:9082 6076:9082 6036:9083 6076:9083 6037:9081 6077:9081 6037:9082 6077:9082 6037:9083 6077:9083 6038:9081 6078:9081 6038:9082 6078:9082 6038:9083 6078:9083 6039:9081 6039:9082 6039:9083 6000:9084 6040:9084 6000:9085 6040:9085 6000:9086 6040:9086 6001:9084 6041:9084 6001:9085 6041:9085 6001:9086 6041:9086 6002:9084 6042:9084 6002:9085 6042:9085 6002:9086 6042:9086 6003:9084 6043:9084 6003:9085 6043:9085 6003:9086 6043:9086 6004:9084 6044:9084 6004:9085 6044:9085 6004:9086 6044:9086 6005:9084 6045:9084 6005:9085 6045:9085 6005:9086 6045:9086 6006:9084 6046:9084 6006:9085 6046:9085 6006:9086 6046:9086 6007:9084 6047:9084 6007:9085 6047:9085 6007:9086 6047:9086 6008:9084 6048:9084 6008:9085 6048:9085 6008:9086 6048:9086 6009:9084 6049:9084 6009:9085 6049:9085 6009:9086 6049:9086 6010:9084 6050:9084 6010:9085 6050:9085 6010:9086 6050:9086 6011:9084 6051:9084 6011:9085 6051:9085 6011:9086 6051:9086 6012:9084 6052:9084 6012:9085 6052:9085 6012:9086 6052:9086 6013:9084 6053:9084 6013:9085 6053:9085 6013:9086 6053:9086 6014:9084 6054:9084 6014:9085 6054:9085 6014:9086 6054:9086 6015:9084 6055:9084 6015:9085 6055:9085 6015:9086 6055:9086 6016:9084 6056:9084 6016:9085 6056:9085 6016:9086 6056:9086 6017:9084 6057:9084 6017:9085 6057:9085 6017:9086 6057:9086 6018:9084 6058:9084 6018:9085 6058:9085 6018:9086 6058:9086 6019:9084 6059:9084 6019:9085 6059:9085 6019:9086 6059:9086 6020:9084 6060:9084 6020:9085 6060:9085 6020:9086 6060:9086 6021:9084 6061:9084 6021:9085 6061:9085 6021:9086 6061:9086 6022:9084 6062:9084 6022:9085 6062:9085 6022:9086 6062:9086 6023:9084 6063:9084 6023:9085 6063:9085 6023:9086 6063:9086 6024:9084 6064:9084 6024:9085 6064:9085 6024:9086 6064:9086 6025:9084 6065:9084 6025:9085 6065:9085 6025:9086 6065:9086 6026:9084 6066:9084 6026:9085 6066:9085 6026:9086 6066:9086 6027:9084 6067:9084 6027:9085 6067:9085 6027:9086 6067:9086 6028:9084 6068:9084 6028:9085 6068:9085 6028:9086 6068:9086 6029:9084 6069:9084 6029:9085 6069:9085 6029:9086 6069:9086 6030:9084 6070:9084 6030:9085 6070:9085 6030:9086 6070:9086 6031:9084 6071:9084 6031:9085 6071:9085 6031:9086 6071:9086 6032:9084 6072:9084 6032:9085 6072:9085 6032:9086 6072:9086 6033:9084 6073:9084 6033:9085 6073:9085 6033:9086 6073:9086 6034:9084 6074:9084 6034:9085 6074:9085 6034:9086 6074:9086 6035:9084 6075:9084 6035:9085 6075:9085 6035:9086 6075:9086 6036:9084 6076:9084 6036:9085 6076:9085 6036:9086 6076:9086 6037:9084 6077:9084 6037:9085 6077:9085 6037:9086 6077:9086 6038:9084 6078:9084 6038:9085 6078:9085 6038:9086 6078:9086 6039:9084 6039:9085 6039:9086 6000:9087 6040:9087 6000:9088 6040:9088 6000:9089 6040:9089 6001:9087 6041:9087 6001:9088 6041:9088 6001:9089 6041:9089 6002:9087 6042:9087 6002:9088 6042:9088 6002:9089 6042:9089 6003:9087 6043:9087 6003:9088 6043:9088 6003:9089 6043:9089 6004:9087 6044:9087 6004:9088 6044:9088 6004:9089 6044:9089 6005:9087 6045:9087 6005:9088 6045:9088 6005:9089 6045:9089 6006:9087 6046:9087 6006:9088 6046:9088 6006:9089 6046:9089 6007:9087 6047:9087 6007:9088 6047:9088 6007:9089 6047:9089 6008:9087 6048:9087 6008:9088 6048:9088 6008:9089 6048:9089 6009:9087 6049:9087 6009:9088 6049:9088 6009:9089 6049:9089 6010:9087 6050:9087 6010:9088 6050:9088 6010:9089 6050:9089 6011:9087 6051:9087 6011:9088 6051:9088 6011:9089 6051:9089 6012:9087 6052:9087 6012:9088 6052:9088 6012:9089 6052:9089 6013:9087 6053:9087 6013:9088 6053:9088 6013:9089 6053:9089 6014:9087 6054:9087 6014:9088 6054:9088 6014:9089 6054:9089 6015:9087 6055:9087 6015:9088 6055:9088 6015:9089 6055:9089 6016:9087 6056:9087 6016:9088 6056:9088 6016:9089 6056:9089 6017:9087 6057:9087 6017:9088 6057:9088 6017:9089 6057:9089 6018:9087 6058:9087 6018:9088 6058:9088 6018:9089 6058:9089 6019:9087 6059:9087 6019:9088 6059:9088 6019:9089 6059:9089 6020:9087 6060:9087 6020:9088 6060:9088 6020:9089 6060:9089 6021:9087 6061:9087 6021:9088 6061:9088 6021:9089 6061:9089 6022:9087 6062:9087 6022:9088 6062:9088 6022:9089 6062:9089 6023:9087 6063:9087 6023:9088 6063:9088 6023:9089 6063:9089 6024:9087 6064:9087 6024:9088 6064:9088 6024:9089 6064:9089 6025:9087 6065:9087 6025:9088 6065:9088 6025:9089 6065:9089 6026:9087 6066:9087 6026:9088 6066:9088 6026:9089 6066:9089 6027:9087 6067:9087 6027:9088 6067:9088 6027:9089 6067:9089 6028:9087 6068:9087 6028:9088 6068:9088 6028:9089 6068:9089 6029:9087 6069:9087 6029:9088 6069:9088 6029:9089 6069:9089 6030:9087 6070:9087 6030:9088 6070:9088 6030:9089 6070:9089 6031:9087 6071:9087 6031:9088 6071:9088 6031:9089 6071:9089 6032:9087 6072:9087 6032:9088 6072:9088 6032:9089 6072:9089 6033:9087 6073:9087 6033:9088 6073:9088 6033:9089 6073:9089 6034:9087 6074:9087 6034:9088 6074:9088 6034:9089 6074:9089 6035:9087 6075:9087 6035:9088 6075:9088 6035:9089 6075:9089 6036:9087 6076:9087 6036:9088 6076:9088 6036:9089 6076:9089 6037:9087 6077:9087 6037:9088 6077:9088 6037:9089 6077:9089 6038:9087 6078:9087 6038:9088 6078:9088 6038:9089 6078:9089 6039:9087 6039:9088 6039:9089 6000:9090 6040:9090 6000:9091 6040:9091 6000:9092 6040:9092 6001:9090 6041:9090 6001:9091 6041:9091 6001:9092 6041:9092 6002:9090 6042:9090 6002:9091 6042:9091 6002:9092 6042:9092 6003:9090 6043:9090 6003:9091 6043:9091 6003:9092 6043:9092 6004:9090 6044:9090 6004:9091 6044:9091 6004:9092 6044:9092 6005:9090 6045:9090 6005:9091 6045:9091 6005:9092 6045:9092 6006:9090 6046:9090 6006:9091 6046:9091 6006:9092 6046:9092 6007:9090 6047:9090 6007:9091 6047:9091 6007:9092 6047:9092 6008:9090 6048:9090 6008:9091 6048:9091 6008:9092 6048:9092 6009:9090 6049:9090 6009:9091 6049:9091 6009:9092 6049:9092 6010:9090 6050:9090 6010:9091 6050:9091 6010:9092 6050:9092 6011:9090 6051:9090 6011:9091 6051:9091 6011:9092 6051:9092 6012:9090 6052:9090 6012:9091 6052:9091 6012:9092 6052:9092 6013:9090 6053:9090 6013:9091 6053:9091 6013:9092 6053:9092 6014:9090 6054:9090 6014:9091 6054:9091 6014:9092 6054:9092 6015:9090 6055:9090 6015:9091 6055:9091 6015:9092 6055:9092 6016:9090 6056:9090 6016:9091 6056:9091 6016:9092 6056:9092 6017:9090 6057:9090 6017:9091 6057:9091 6017:9092 6057:9092 6018:9090 6058:9090 6018:9091 6058:9091 6018:9092 6058:9092 6019:9090 6059:9090 6019:9091 6059:9091 6019:9092 6059:9092 6020:9090 6060:9090 6020:9091 6060:9091 6020:9092 6060:9092 6021:9090 6061:9090 6021:9091 6061:9091 6021:9092 6061:9092 6022:9090 6062:9090 6022:9091 6062:9091 6022:9092 6062:9092 6023:9090 6063:9090 6023:9091 6063:9091 6023:9092 6063:9092 6024:9090 6064:9090 6024:9091 6064:9091 6024:9092 6064:9092 6025:9090 6065:9090 6025:9091 6065:9091 6025:9092 6065:9092 6026:9090 6066:9090 6026:9091 6066:9091 6026:9092 6066:9092 6027:9090 6067:9090 6027:9091 6067:9091 6027:9092 6067:9092 6028:9090 6068:9090 6028:9091 6068:9091 6028:9092 6068:9092 6029:9090 6069:9090 6029:9091 6069:9091 6029:9092 6069:9092 6030:9090 6070:9090 6030:9091 6070:9091 6030:9092 6070:9092 6031:9090 6071:9090 6031:9091 6071:9091 6031:9092 6071:9092 6032:9090 6072:9090 6032:9091 6072:9091 6032:9092 6072:9092 6033:9090 6073:9090 6033:9091 6073:9091 6033:9092 6073:9092 6034:9090 6074:9090 6034:9091 6074:9091 6034:9092 6074:9092 6035:9090 6075:9090 6035:9091 6075:9091 6035:9092 6075:9092 6036:9090 6076:9090 6036:9091 6076:9091 6036:9092 6076:9092 6037:9090 6077:9090 6037:9091 6077:9091 6037:9092 6077:9092 6038:9090 6078:9090 6038:9091 6078:9091 6038:9092 6078:9092 6039:9090 6039:9091 6039:9092 6000:9093 6040:9093 6000:9094 6040:9094 6000:9095 6040:9095 6001:9093 6041:9093 6001:9094 6041:9094 6001:9095 6041:9095 6002:9093 6042:9093 6002:9094 6042:9094 6002:9095 6042:9095 6003:9093 6043:9093 6003:9094 6043:9094 6003:9095 6043:9095 6004:9093 6044:9093 6004:9094 6044:9094 6004:9095 6044:9095 6005:9093 6045:9093 6005:9094 6045:9094 6005:9095 6045:9095 6006:9093 6046:9093 6006:9094 6046:9094 6006:9095 6046:9095 6007:9093 6047:9093 6007:9094 6047:9094 6007:9095 6047:9095 6008:9093 6048:9093 6008:9094 6048:9094 6008:9095 6048:9095 6009:9093 6049:9093 6009:9094 6049:9094 6009:9095 6049:9095 6010:9093 6050:9093 6010:9094 6050:9094 6010:9095 6050:9095 6011:9093 6051:9093 6011:9094 6051:9094 6011:9095 6051:9095 6012:9093 6052:9093 6012:9094 6052:9094 6012:9095 6052:9095 6013:9093 6053:9093 6013:9094 6053:9094 6013:9095 6053:9095 6014:9093 6054:9093 6014:9094 6054:9094 6014:9095 6054:9095 6015:9093 6055:9093 6015:9094 6055:9094 6015:9095 6055:9095 6016:9093 6056:9093 6016:9094 6056:9094 6016:9095 6056:9095 6017:9093 6057:9093 6017:9094 6057:9094 6017:9095 6057:9095 6018:9093 6058:9093 6018:9094 6058:9094 6018:9095 6058:9095 6019:9093 6059:9093 6019:9094 6059:9094 6019:9095 6059:9095 6020:9093 6060:9093 6020:9094 6060:9094 6020:9095 6060:9095 6021:9093 6061:9093 6021:9094 6061:9094 6021:9095 6061:9095 6022:9093 6062:9093 6022:9094 6062:9094 6022:9095 6062:9095 6023:9093 6063:9093 6023:9094 6063:9094 6023:9095 6063:9095 6024:9093 6064:9093 6024:9094 6064:9094 6024:9095 6064:9095 6025:9093 6065:9093 6025:9094 6065:9094 6025:9095 6065:9095 6026:9093 6066:9093 6026:9094 6066:9094 6026:9095 6066:9095 6027:9093 6067:9093 6027:9094 6067:9094 6027:9095 6067:9095 6028:9093 6068:9093 6028:9094 6068:9094 6028:9095 6068:9095 6029:9093 6069:9093 6029:9094 6069:9094 6029:9095 6069:9095 6030:9093 6070:9093 6030:9094 6070:9094 6030:9095 6070:9095 6031:9093 6071:9093 6031:9094 6071:9094 6031:9095 6071:9095 6032:9093 6072:9093 6032:9094 6072:9094 6032:9095 6072:9095 6033:9093 6073:9093 6033:9094 6073:9094 6033:9095 6073:9095 6034:9093 6074:9093 6034:9094 6074:9094 6034:9095 6074:9095 6035:9093 6075:9093 6035:9094 6075:9094 6035:9095 6075:9095 6036:9093 6076:9093 6036:9094 6076:9094 6036:9095 6076:9095 6037:9093 6077:9093 6037:9094 6077:9094 6037:9095 6077:9095 6038:9093 6078:9093 6038:9094 6078:9094 6038:9095 6078:9095 6039:9093 6039:9094 6039:9095 6000:9096 6040:9096 6000:9097 6040:9097 6000:9098 6040:9098 6001:9096 6041:9096 6001:9097 6041:9097 6001:9098 6041:9098 6002:9096 6042:9096 6002:9097 6042:9097 6002:9098 6042:9098 6003:9096 6043:9096 6003:9097 6043:9097 6003:9098 6043:9098 6004:9096 6044:9096 6004:9097 6044:9097 6004:9098 6044:9098 6005:9096 6045:9096 6005:9097 6045:9097 6005:9098 6045:9098 6006:9096 6046:9096 6006:9097 6046:9097 6006:9098 6046:9098 6007:9096 6047:9096 6007:9097 6047:9097 6007:9098 6047:9098 6008:9096 6048:9096 6008:9097 6048:9097 6008:9098 6048:9098 6009:9096 6049:9096 6009:9097 6049:9097 6009:9098 6049:9098 6010:9096 6050:9096 6010:9097 6050:9097 6010:9098 6050:9098 6011:9096 6051:9096 6011:9097 6051:9097 6011:9098 6051:9098 6012:9096 6052:9096 6012:9097 6052:9097 6012:9098 6052:9098 6013:9096 6053:9096 6013:9097 6053:9097 6013:9098 6053:9098 6014:9096 6054:9096 6014:9097 6054:9097 6014:9098 6054:9098 6015:9096 6055:9096 6015:9097 6055:9097 6015:9098 6055:9098 6016:9096 6056:9096 6016:9097 6056:9097 6016:9098 6056:9098 6017:9096 6057:9096 6017:9097 6057:9097 6017:9098 6057:9098 6018:9096 6058:9096 6018:9097 6058:9097 6018:9098 6058:9098 6019:9096 6059:9096 6019:9097 6059:9097 6019:9098 6059:9098 6020:9096 6060:9096 6020:9097 6060:9097 6020:9098 6060:9098 6021:9096 6061:9096 6021:9097 6061:9097 6021:9098 6061:9098 6022:9096 6062:9096 6022:9097 6062:9097 6022:9098 6062:9098 6023:9096 6063:9096 6023:9097 6063:9097 6023:9098 6063:9098 6024:9096 6064:9096 6024:9097 6064:9097 6024:9098 6064:9098 6025:9096 6065:9096 6025:9097 6065:9097 6025:9098 6065:9098 6026:9096 6066:9096 6026:9097 6066:9097 6026:9098 6066:9098 6027:9096 6067:9096 6027:9097 6067:9097 6027:9098 6067:9098 6028:9096 6068:9096 6028:9097 6068:9097 6028:9098 6068:9098 6029:9096 6069:9096 6029:9097 6069:9097 6029:9098 6069:9098 6030:9096 6070:9096 6030:9097 6070:9097 6030:9098 6070:9098 6031:9096 6071:9096 6031:9097 6071:9097 6031:9098 6071:9098 6032:9096 6072:9096 6032:9097 6072:9097 6032:9098 6072:9098 6033:9096 6073:9096 6033:9097 6073:9097 6033:9098 6073:9098 6034:9096 6074:9096 6034:9097 6074:9097 6034:9098 6074:9098 6035:9096 6075:9096 6035:9097 6075:9097 6035:9098 6075:9098 6036:9096 6076:9096 6036:9097 6076:9097 6036:9098 6076:9098 6037:9096 6077:9096 6037:9097 6077:9097 6037:9098 6077:9098 6038:9096 6078:9096 6038:9097 6078:9097 6038:9098 6078:9098 6039:9096 6039:9097 6039:9098 6000:9099 6040:9099 6000:9100 6040:9100 6000:9101 6040:9101 6001:9099 6041:9099 6001:9100 6041:9100 6001:9101 6041:9101 6002:9099 6042:9099 6002:9100 6042:9100 6002:9101 6042:9101 6003:9099 6043:9099 6003:9100 6043:9100 6003:9101 6043:9101 6004:9099 6044:9099 6004:9100 6044:9100 6004:9101 6044:9101 6005:9099 6045:9099 6005:9100 6045:9100 6005:9101 6045:9101 6006:9099 6046:9099 6006:9100 6046:9100 6006:9101 6046:9101 6007:9099 6047:9099 6007:9100 6047:9100 6007:9101 6047:9101 6008:9099 6048:9099 6008:9100 6048:9100 6008:9101 6048:9101 6009:9099 6049:9099 6009:9100 6049:9100 6009:9101 6049:9101 6010:9099 6050:9099 6010:9100 6050:9100 6010:9101 6050:9101 6011:9099 6051:9099 6011:9100 6051:9100 6011:9101 6051:9101 6012:9099 6052:9099 6012:9100 6052:9100 6012:9101 6052:9101 6013:9099 6053:9099 6013:9100 6053:9100 6013:9101 6053:9101 6014:9099 6054:9099 6014:9100 6054:9100 6014:9101 6054:9101 6015:9099 6055:9099 6015:9100 6055:9100 6015:9101 6055:9101 6016:9099 6056:9099 6016:9100 6056:9100 6016:9101 6056:9101 6017:9099 6057:9099 6017:9100 6057:9100 6017:9101 6057:9101 6018:9099 6058:9099 6018:9100 6058:9100 6018:9101 6058:9101 6019:9099 6059:9099 6019:9100 6059:9100 6019:9101 6059:9101 6020:9099 6060:9099 6020:9100 6060:9100 6020:9101 6060:9101 6021:9099 6061:9099 6021:9100 6061:9100 6021:9101 6061:9101 6022:9099 6062:9099 6022:9100 6062:9100 6022:9101 6062:9101 6023:9099 6063:9099 6023:9100 6063:9100 6023:9101 6063:9101 6024:9099 6064:9099 6024:9100 6064:9100 6024:9101 6064:9101 6025:9099 6065:9099 6025:9100 6065:9100 6025:9101 6065:9101 6026:9099 6066:9099 6026:9100 6066:9100 6026:9101 6066:9101 6027:9099 6067:9099 6027:9100 6067:9100 6027:9101 6067:9101 6028:9099 6068:9099 6028:9100 6068:9100 6028:9101 6068:9101 6029:9099 6069:9099 6029:9100 6069:9100 6029:9101 6069:9101 6030:9099 6070:9099 6030:9100 6070:9100 6030:9101 6070:9101 6031:9099 6071:9099 6031:9100 6071:9100 6031:9101 6071:9101 6032:9099 6072:9099 6032:9100 6072:9100 6032:9101 6072:9101 6033:9099 6073:9099 6033:9100 6073:9100 6033:9101 6073:9101 6034:9099 6074:9099 6034:9100 6074:9100 6034:9101 6074:9101 6035:9099 6075:9099 6035:9100 6075:9100 6035:9101 6075:9101 6036:9099 6076:9099 6036:9100 6076:9100 6036:9101 6076:9101 6037:9099 6077:9099 6037:9100 6077:9100 6037:9101 6077:9101 6038:9099 6078:9099 6038:9100 6078:9100 6038:9101 6078:9101 6039:9099 6039:9100 6039:9101 6000:9102 6040:9102 6000:9103 6040:9103 6000:9104 6040:9104 6001:9102 6041:9102 6001:9103 6041:9103 6001:9104 6041:9104 6002:9102 6042:9102 6002:9103 6042:9103 6002:9104 6042:9104 6003:9102 6043:9102 6003:9103 6043:9103 6003:9104 6043:9104 6004:9102 6044:9102 6004:9103 6044:9103 6004:9104 6044:9104 6005:9102 6045:9102 6005:9103 6045:9103 6005:9104 6045:9104 6006:9102 6046:9102 6006:9103 6046:9103 6006:9104 6046:9104 6007:9102 6047:9102 6007:9103 6047:9103 6007:9104 6047:9104 6008:9102 6048:9102 6008:9103 6048:9103 6008:9104 6048:9104 6009:9102 6049:9102 6009:9103 6049:9103 6009:9104 6049:9104 6010:9102 6050:9102 6010:9103 6050:9103 6010:9104 6050:9104 6011:9102 6051:9102 6011:9103 6051:9103 6011:9104 6051:9104 6012:9102 6052:9102 6012:9103 6052:9103 6012:9104 6052:9104 6013:9102 6053:9102 6013:9103 6053:9103 6013:9104 6053:9104 6014:9102 6054:9102 6014:9103 6054:9103 6014:9104 6054:9104 6015:9102 6055:9102 6015:9103 6055:9103 6015:9104 6055:9104 6016:9102 6056:9102 6016:9103 6056:9103 6016:9104 6056:9104 6017:9102 6057:9102 6017:9103 6057:9103 6017:9104 6057:9104 6018:9102 6058:9102 6018:9103 6058:9103 6018:9104 6058:9104 6019:9102 6059:9102 6019:9103 6059:9103 6019:9104 6059:9104 6020:9102 6060:9102 6020:9103 6060:9103 6020:9104 6060:9104 6021:9102 6061:9102 6021:9103 6061:9103 6021:9104 6061:9104 6022:9102 6062:9102 6022:9103 6062:9103 6022:9104 6062:9104 6023:9102 6063:9102 6023:9103 6063:9103 6023:9104 6063:9104 6024:9102 6064:9102 6024:9103 6064:9103 6024:9104 6064:9104 6025:9102 6065:9102 6025:9103 6065:9103 6025:9104 6065:9104 6026:9102 6066:9102 6026:9103 6066:9103 6026:9104 6066:9104 6027:9102 6067:9102 6027:9103 6067:9103 6027:9104 6067:9104 6028:9102 6068:9102 6028:9103 6068:9103 6028:9104 6068:9104 6029:9102 6069:9102 6029:9103 6069:9103 6029:9104 6069:9104 6030:9102 6070:9102 6030:9103 6070:9103 6030:9104 6070:9104 6031:9102 6071:9102 6031:9103 6071:9103 6031:9104 6071:9104 6032:9102 6072:9102 6032:9103 6072:9103 6032:9104 6072:9104 6033:9102 6073:9102 6033:9103 6073:9103 6033:9104 6073:9104 6034:9102 6074:9102 6034:9103 6074:9103 6034:9104 6074:9104 6035:9102 6075:9102 6035:9103 6075:9103 6035:9104 6075:9104 6036:9102 6076:9102 6036:9103 6076:9103 6036:9104 6076:9104 6037:9102 6077:9102 6037:9103 6077:9103 6037:9104 6077:9104 6038:9102 6078:9102 6038:9103 6078:9103 6038:9104 6078:9104 6039:9102 6039:9103 6039:9104 6000:9105 6040:9105 — — — — 6001:9105 6041:9105 6002:9105 6042:9105 6003:9105 6043:9105 6004:9105 6044:9105 6005:9105 6045:9105 6006:9105 6046:9105 6007:9105 6047:9105 6008:9105 6048:9105 6009:9105 6049:9105 6010:9105 6050:9105 6011:9105 6051:9105 6012:9105 6052:9105 6013:9105 6053:9105 6014:9105 6054:9105 6015:9105 6055:9105 6016:9105 6056:9105 6017:9105 6057:9105 6018:9105 6058:9105 6019:9105 6059:9105 6020:9105 6060:9105 6021:9105 6061:9105 6022:9105 6062:9105 6023:9105 6063:9105 6024:9105 6064:9105 6025:9105 6065:9105 6026:9105 6066:9105 6027:9105 6067:9105 6028:9105 6068:9105 6029:9105 6069:9105 6030:9105 6070:9105 6031:9105 6071:9105 6032:9105 6072:9105 6033:9105 6073:9105 6034:9105 6074:9105 6035:9105 6075:9105 6036:9105 6076:9105 6037:9105 6077:9105 6038:9105 6078:9105 6039:9105

TABLE E Example combinations of a compound X with a compound Y. X:Y X:Y X:Y X:Y X:Y X:Y 8000:9000 8000:9001 8000:9002 8000:9003 8000:9004 8000:9005 8001:9000 8001:9001 8001:9002 8001:9003 8001:9004 8001:9005 8002:9000 8002:9001 8002:9002 8002:9003 8002:9004 8002:9005 8003:9000 8003:9001 8003:9002 8003:9003 8003:9004 8003:9005 8004:9000 8004:9001 8004:9002 8004:9003 8004:9004 8004:9005 8005:9000 8005:9001 8005:9002 8005:9003 8005:9004 8005:9005 8006:9000 8006:9001 8006:9002 8006:9003 8006:9004 8006:9005 8007:9000 8007:9001 8007:9002 8007:9003 8007:9004 8007:9005 8008:9000 8008:9001 8008:9002 8008:9003 8008:9004 8008:9005 8009:9000 8009:9001 8009:9002 8009:9003 8009:9004 8009:9005 8010:9000 8010:9001 8010:9002 8010:9003 8010:9004 8010:9005 8011:9000 8011:9001 8011:9002 8011:9003 8011:9004 8011:9005 8012:9000 8012:9001 8012:9002 8012:9003 8012:9004 8012:9005 8013:9000 8013:9001 8013:9002 8013:9003 8013:9004 8013:9005 8014:9000 8014:9001 8014:9002 8014:9003 8014:9004 8014:9005 8015:9000 8015:9001 8015:9002 8015:9003 8015:9004 8015:9005 8016:9000 8016:9001 8016:9002 8016:9003 8016:9004 8016:9005 8000:9006 8000:9007 8000:9008 8000:9009 8000:9010 8000:9011 8001:9006 8001:9007 8001:9008 8001:9009 8001:9010 8001:9011 8002:9006 8002:9007 8002:9008 8002:9009 8002:9010 8002:9011 8003:9006 8003:9007 8003:9008 8003:9009 8003:9010 8003:9011 8004:9006 8004:9007 8004:9008 8004:9009 8004:9010 8004:9011 8005:9006 8005:9007 8005:9008 8005:9009 8005:9010 8005:9011 8006:9006 8006:9007 8006:9008 8006:9009 8006:9010 8006:9011 8007:9006 8007:9007 8007:9008 8007:9009 8007:9010 8007:9011 8008:9006 8008:9007 8008:9008 8008:9009 8008:9010 8008:9011 8009:9006 8009:9007 8009:9008 8009:9009 8009:9010 8009:9011 8010:9006 8010:9007 8010:9008 8010:9009 8010:9010 8010:9011 8011:9006 8011:9007 8011:9008 8011:9009 8011:9010 8011:9011 8012:9006 8012:9007 8012:9008 8012:9009 8012:9010 8012:9011 8013:9006 8013:9007 8013:9008 8013:9009 8013:9010 8013:9011 8014:9006 8014:9007 8014:9008 8014:9009 8014:9010 8014:9011 8015:9006 8015:9007 8015:9008 8015:9009 8015:9010 8015:9011 8016:9006 8016:9007 8016:9008 8016:9009 8016:9010 8016:9011 8000:9012 8000:9013 8000:9014 8000:9015 8000:9016 8000:9017 8001:9012 8001:9013 8001:9014 8001:9015 8001:9016 8001:9017 8002:9012 8002:9013 8002:9014 8002:9015 8002:9016 8002:9017 8003:9012 8003:9013 8003:9014 8003:9015 8003:9016 8003:9017 8004:9012 8004:9013 8004:9014 8004:9015 8004:9016 8004:9017 8005:9012 8005:9013 8005:9014 8005:9015 8005:9016 8005:9017 8006:9012 8006:9013 8006:9014 8006:9015 8006:9016 8006:9017 8007:9012 8007:9013 8007:9014 8007:9015 8007:9016 8007:9017 8008:9012 8008:9013 8008:9014 8008:9015 8008:9016 8008:9017 8009:9012 8009:9013 8009:9014 8009:9015 8009:9016 8009:9017 8010:9012 8010:9013 8010:9014 8010:9015 8010:9016 8010:9017 8011:9012 8011:9013 8011:9014 8011:9015 8011:9016 8011:9017 8012:9012 8012:9013 8012:9014 8012:9015 8012:9016 8012:9017 8013:9012 8013:9013 8013:9014 8013:9015 8013:9016 8013:9017 8014:9012 8014:9013 8014:9014 8014:9015 8014:9016 8014:9017 8015:9012 8015:9013 8015:9014 8015:9015 8015:9016 8015:9017 8016:9012 8016:9013 8016:9014 8016:9015 8016:9016 8016:9017 8000:9018 8000:9019 8000:9020 8000:9021 8000:9022 8000:9023 8001:9018 8001:9019 8001:9020 8001:9021 8001:9022 8001:9023 8002:9018 8002:9019 8002:9020 8002:9021 8002:9022 8002:9023 8003:9018 8003:9019 8003:9020 8003:9021 8003:9022 8003:9023 8004:9018 8004:9019 8004:9020 8004:9021 8004:9022 8004:9023 8005:9018 8005:9019 8005:9020 8005:9021 8005:9022 8005:9023 8006:9018 8006:9019 8006:9020 8006:9021 8006:9022 8006:9023 8007:9018 8007:9019 8007:9020 8007:9021 8007:9022 8007:9023 8008:9018 8008:9019 8008:9020 8008:9021 8008:9022 8008:9023 8009:9018 8009:9019 8009:9020 8009:9021 8009:9022 8009:9023 8010:9018 8010:9019 8010:9020 8010:9021 8010:9022 8010:9023 8011:9018 8011:9019 8011:9020 8011:9021 8011:9022 8011:9023 8012:9018 8012:9019 8012:9020 8012:9021 8012:9022 8012:9023 8013:9018 8013:9019 8013:9020 8013:9021 8013:9022 8013:9023 8014:9018 8014:9019 8014:9020 8014:9021 8014:9022 8014:9023 8015:9018 8015:9019 8015:9020 8015:9021 8015:9022 8015:9023 8016:9018 8016:9019 8016:9020 8016:9021 8016:9022 8016:9023 8000:9024 8000:9025 8000:9026 8000:9027 8000:9028 8000:9029 8001:9024 8001:9025 8001:9026 8001:9027 8001:9028 8001:9029 8002:9024 8002:9025 8002:9026 8002:9027 8002:9028 8002:9029 8003:9024 8003:9025 8003:9026 8003:9027 8003:9028 8003:9029 8004:9024 8004:9025 8004:9026 8004:9027 8004:9028 8004:9029 8005:9024 8005:9025 8005:9026 8005:9027 8005:9028 8005:9029 8006:9024 8006:9025 8006:9026 8006:9027 8006:9028 8006:9029 8007:9024 8007:9025 8007:9026 8007:9027 8007:9028 8007:9029 8008:9024 8008:9025 8008:9026 8008:9027 8008:9028 8008:9029 8009:9024 8009:9025 8009:9026 8009:9027 8009:9028 8009:9029 8010:9024 8010:9025 8010:9026 8010:9027 8010:9028 8010:9029 8011:9024 8011:9025 8011:9026 8011:9027 8011:9028 8011:9029 8012:9024 8012:9025 8012:9026 8012:9027 8012:9028 8012:9029 8013:9024 8013:9025 8013:9026 8013:9027 8013:9028 8013:9029 8014:9024 8014:9025 8014:9026 8014:9027 8014:9028 8014:9029 8015:9024 8015:9025 8015:9026 8015:9027 8015:9028 8015:9029 8016:9024 8016:9025 8016:9026 8016:9027 8016:9028 8016:9029 8000:9030 8000:9031 8000:9032 8000:9033 8000:9034 8000:9035 8001:9030 8001:9031 8001:9032 8001:9033 8001:9034 8001:9035 8002:9030 8002:9031 8002:9032 8002:9033 8002:9034 8002:9035 8003:9030 8003:9031 8003:9032 8003:9033 8003:9034 8003:9035 8004:9030 8004:9031 8004:9032 8004:9033 8004:9034 8004:9035 8005:9030 8005:9031 8005:9032 8005:9033 8005:9034 8005:9035 8006:9030 8006:9031 8006:9032 8006:9033 8006:9034 8006:9035 8007:9030 8007:9031 8007:9032 8007:9033 8007:9034 8007:9035 8008:9030 8008:9031 8008:9032 8008:9033 8008:9034 8008:9035 8009:9030 8009:9031 8009:9032 8009:9033 8009:9034 8009:9035 8010:9030 8010:9031 8010:9032 8010:9033 8010:9034 8010:9035 8011:9030 8011:9031 8011:9032 8011:9033 8011:9034 8011:9035 8012:9030 8012:9031 8012:9032 8012:9033 8012:9034 8012:9035 8013:9030 8013:9031 8013:9032 8013:9033 8013:9034 8013:9035 8014:9030 8014:9031 8014:9032 8014:9033 8014:9034 8014:9035 8015:9030 8015:9031 8015:9032 8015:9033 8015:9034 8015:9035 8016:9030 8016:9031 8016:9032 8016:9033 8016:9034 8016:9035 8000:9036 8000:9037 8000:9038 8000:9039 8000:9040 8000:9041 8001:9036 8001:9037 8001:9038 8001:9039 8001:9040 8001:9041 8002:9036 8002:9037 8002:9038 8002:9039 8002:9040 8002:9041 8003:9036 8003:9037 8003:9038 8003:9039 8003:9040 8003:9041 8004:9036 8004:9037 8004:9038 8004:9039 8004:9040 8004:9041 8005:9036 8005:9037 8005:9038 8005:9039 8005:9040 8005:9041 8006:9036 8006:9037 8006:9038 8006:9039 8006:9040 8006:9041 8007:9036 8007:9037 8007:9038 8007:9039 8007:9040 8007:9041 8008:9036 8008:9037 8008:9038 8008:9039 8008:9040 8008:9041 8009:9036 8009:9037 8009:9038 8009:9039 8009:9040 8009:9041 8010:9036 8010:9037 8010:9038 8010:9039 8010:9040 8010:9041 8011:9036 8011:9037 8011:9038 8011:9039 8011:9040 8011:9041 8012:9036 8012:9037 8012:9038 8012:9039 8012:9040 8012:9041 8013:9036 8013:9037 8013:9038 8013:9039 8013:9040 8013:9041 8014:9036 8014:9037 8014:9038 8014:9039 8014:9040 8014:9041 8015:9036 8015:9037 8015:9038 8015:9039 8015:9040 8015:9041 8016:9036 8016:9037 8016:9038 8016:9039 8016:9040 8016:9041 8000:9042 8000:9043 8000:9044 8000:9045 8000:9046 8000:9047 8001:9042 8001:9043 8001:9044 8001:9045 8001:9046 8001:9047 8002:9042 8002:9043 8002:9044 8002:9045 8002:9046 8002:9047 8003:9042 8003:9043 8003:9044 8003:9045 8003:9046 8003:9047 8004:9042 8004:9043 8004:9044 8004:9045 8004:9046 8004:9047 8005:9042 8005:9043 8005:9044 8005:9045 8005:9046 8005:9047 8006:9042 8006:9043 8006:9044 8006:9045 8006:9046 8006:9047 8007:9042 8007:9043 8007:9044 8007:9045 8007:9046 8007:9047 8008:9042 8008:9043 8008:9044 8008:9045 8008:9046 8008:9047 8009:9042 8009:9043 8009:9044 8009:9045 8009:9046 8009:9047 8010:9042 8010:9043 8010:9044 8010:9045 8010:9046 8010:9047 8011:9042 8011:9043 8011:9044 8011:9045 8011:9046 8011:9047 8012:9042 8012:9043 8012:9044 8012:9045 8012:9046 8012:9047 8013:9042 8013:9043 8013:9044 8013:9045 8013:9046 8013:9047 8014:9042 8014:9043 8014:9044 8014:9045 8014:9046 8014:9047 8015:9042 8015:9043 8015:9044 8015:9045 8015:9046 8015:9047 8016:9042 8016:9043 8016:9044 8016:9045 8016:9046 8016:9047 8000:9048 8000:9049 8000:9050 8000:9051 8000:9052 8000:9053 8001:9048 8001:9049 8001:9050 8001:9051 8001:9052 8001:9053 8002:9048 8002:9049 8002:9050 8002:9051 8002:9052 8002:9053 8003:9048 8003:9049 8003:9050 8003:9051 8003:9052 8003:9053 8004:9048 8004:9049 8004:9050 8004:9051 8004:9052 8004:9053 8005:9048 8005:9049 8005:9050 8005:9051 8005:9052 8005:9053 8006:9048 8006:9049 8006:9050 8006:9051 8006:9052 8006:9053 8007:9048 8007:9049 8007:9050 8007:9051 8007:9052 8007:9053 8008:9048 8008:9049 8008:9050 8008:9051 8008:9052 8008:9053 8009:9048 8009:9049 8009:9050 8009:9051 8009:9052 8009:9053 8010:9048 8010:9049 8010:9050 8010:9051 8010:9052 8010:9053 8011:9048 8011:9049 8011:9050 8011:9051 8011:9052 8011:9053 8012:9048 8012:9049 8012:9050 8012:9051 8012:9052 8012:9053 8013:9048 8013:9049 8013:9050 8013:9051 8013:9052 8013:9053 8014:9048 8014:9049 8014:9050 8014:9051 8014:9052 8014:9053 8015:9048 8015:9049 8015:9050 8015:9051 8015:9052 8015:9053 8016:9048 8016:9049 8016:9050 8016:9051 8016:9052 8016:9053 8000:9054 8000:9055 8000:9056 8000:9057 8000:9058 8000:9059 8001:9054 8001:9055 8001:9056 8001:9057 8001:9058 8001:9059 8002:9054 8002:9055 8002:9056 8002:9057 8002:9058 8002:9059 8003:9054 8003:9055 8003:9056 8003:9057 8003:9058 8003:9059 8004:9054 8004:9055 8004:9056 8004:9057 8004:9058 8004:9059 8005:9054 8005:9055 8005:9056 8005:9057 8005:9058 8005:9059 8006:9054 8006:9055 8006:9056 8006:9057 8006:9058 8006:9059 8007:9054 8007:9055 8007:9056 8007:9057 8007:9058 8007:9059 8008:9054 8008:9055 8008:9056 8008:9057 8008:9058 8008:9059 8009:9054 8009:9055 8009:9056 8009:9057 8009:9058 8009:9059 8010:9054 8010:9055 8010:9056 8010:9057 8010:9058 8010:9059 8011:9054 8011:9055 8011:9056 8011:9057 8011:9058 8011:9059 8012:9054 8012:9055 8012:9056 8012:9057 8012:9058 8012:9059 8013:9054 8013:9055 8013:9056 8013:9057 8013:9058 8013:9059 8014:9054 8014:9055 8014:9056 8014:9057 8014:9058 8014:9059 8015:9054 8015:9055 8015:9056 8015:9057 8015:9058 8015:9059 8016:9054 8016:9055 8016:9056 8016:9057 8016:9058 8016:9059 8000:9060 8000:9061 8000:9062 8000:9063 8000:9064 8000:9065 8001:9060 8001:9061 8001:9062 8001:9063 8001:9064 8001:9065 8002:9060 8002:9061 8002:9062 8002:9063 8002:9064 8002:9065 8003:9060 8003:9061 8003:9062 8003:9063 8003:9064 8003:9065 8004:9060 8004:9061 8004:9062 8004:9063 8004:9064 8004:9065 8005:9060 8005:9061 8005:9062 8005:9063 8005:9064 8005:9065 8006:9060 8006:9061 8006:9062 8006:9063 8006:9064 8006:9065 8007:9060 8007:9061 8007:9062 8007:9063 8007:9064 8007:9065 8008:9060 8008:9061 8008:9062 8008:9063 8008:9064 8008:9065 8009:9060 8009:9061 8009:9062 8009:9063 8009:9064 8009:9065 8010:9060 8010:9061 8010:9062 8010:9063 8010:9064 8010:9065 8011:9060 8011:9061 8011:9062 8011:9063 8011:9064 8011:9065 8012:9060 8012:9061 8012:9062 8012:9063 8012:9064 8012:9065 8013:9060 8013:9061 8013:9062 8013:9063 8013:9064 8013:9065 8014:9060 8014:9061 8014:9062 8014:9063 8014:9064 8014:9065 8015:9060 8015:9061 8015:9062 8015:9063 8015:9064 8015:9065 8016:9060 8016:9061 8016:9062 8016:9063 8016:9064 8016:9065 8000:9066 8000:9067 8000:9068 8000:9069 8000:9070 8000:9071 8001:9066 8001:9067 8001:9068 8001:9069 8001:9070 8001:9071 8002:9066 8002:9067 8002:9068 8002:9069 8002:9070 8002:9071 8003:9066 8003:9067 8003:9068 8003:9069 8003:9070 8003:9071 8004:9066 8004:9067 8004:9068 8004:9069 8004:9070 8004:9071 8005:9066 8005:9067 8005:9068 8005:9069 8005:9070 8005:9071 8006:9066 8006:9067 8006:9068 8006:9069 8006:9070 8006:9071 8007:9066 8007:9067 8007:9068 8007:9069 8007:9070 8007:9071 8008:9066 8008:9067 8008:9068 8008:9069 8008:9070 8008:9071 8009:9066 8009:9067 8009:9068 8009:9069 8009:9070 8009:9071 8010:9066 8010:9067 8010:9068 8010:9069 8010:9070 8010:9071 8011:9066 8011:9067 8011:9068 8011:9069 8011:9070 8011:9071 8012:9066 8012:9067 8012:9068 8012:9069 8012:9070 8012:9071 8013:9066 8013:9067 8013:9068 8013:9069 8013:9070 8013:9071 8014:9066 8014:9067 8014:9068 8014:9069 8014:9070 8014:9071 8015:9066 8015:9067 8015:9068 8015:9069 8015:9070 8015:9071 8016:9066 8016:9067 8016:9068 8016:9069 8016:9070 8016:9071 8000:9072 8000:9073 8000:9074 8000:9075 8000:9076 8000:9077 8001:9072 8001:9073 8001:9074 8001:9075 8001:9076 8001:9077 8002:9072 8002:9073 8002:9074 8002:9075 8002:9076 8002:9077 8003:9072 8003:9073 8003:9074 8003:9075 8003:9076 8003:9077 8004:9072 8004:9073 8004:9074 8004:9075 8004:9076 8004:9077 8005:9072 8005:9073 8005:9074 8005:9075 8005:9076 8005:9077 8006:9072 8006:9073 8006:9074 8006:9075 8006:9076 8006:9077 8007:9072 8007:9073 8007:9074 8007:9075 8007:9076 8007:9077 8008:9072 8008:9073 8008:9074 8008:9075 8008:9076 8008:9077 8009:9072 8009:9073 8009:9074 8009:9075 8009:9076 8009:9077 8010:9072 8010:9073 8010:9074 8010:9075 8010:9076 8010:9077 8011:9072 8011:9073 8011:9074 8011:9075 8011:9076 8011:9077 8012:9072 8012:9073 8012:9074 8012:9075 8012:9076 8012:9077 8013:9072 8013:9073 8013:9074 8013:9075 8013:9076 8013:9077 8014:9072 8014:9073 8014:9074 8014:9075 8014:9076 8014:9077 8015:9072 8015:9073 8015:9074 8015:9075 8015:9076 8015:9077 8016:9072 8016:9073 8016:9074 8016:9075 8016:9076 8016:9077 8000:9078 8000:9079 8000:9080 8000:9081 8000:9082 8000:9083 8001:9078 8001:9079 8001:9080 8001:9081 8001:9082 8001:9083 8002:9078 8002:9079 8002:9080 8002:9081 8002:9082 8002:9083 8003:9078 8003:9079 8003:9080 8003:9081 8003:9082 8003:9083 8004:9078 8004:9079 8004:9080 8004:9081 8004:9082 8004:9083 8005:9078 8005:9079 8005:9080 8005:9081 8005:9082 8005:9083 8006:9078 8006:9079 8006:9080 8006:9081 8006:9082 8006:9083 8007:9078 8007:9079 8007:9080 8007:9081 8007:9082 8007:9083 8008:9078 8008:9079 8008:9080 8008:9081 8008:9082 8008:9083 8009:9078 8009:9079 8009:9080 8009:9081 8009:9082 8009:9083 8010:9078 8010:9079 8010:9080 8010:9081 8010:9082 8010:9083 8011:9078 8011:9079 8011:9080 8011:9081 8011:9082 8011:9083 8012:9078 8012:9079 8012:9080 8012:9081 8012:9082 8012:9083 8013:9078 8013:9079 8013:9080 8013:9081 8013:9082 8013:9083 8014:9078 8014:9079 8014:9080 8014:9081 8014:9082 8014:9083 8015:9078 8015:9079 8015:9080 8015:9081 8015:9082 8015:9083 8016:9078 8016:9079 8016:9080 8016:9081 8016:9082 8016:9083 8000:9084 8000:9085 8000:9086 8000:9087 8000:9088 8000:9089 8001:9084 8001:9085 8001:9086 8001:9087 8001:9088 8001:9089 8002:9084 8002:9085 8002:9086 8002:9087 8002:9088 8002:9089 8003:9084 8003:9085 8003:9086 8003:9087 8003:9088 8003:9089 8004:9084 8004:9085 8004:9086 8004:9087 8004:9088 8004:9089 8005:9084 8005:9085 8005:9086 8005:9087 8005:9088 8005:9089 8006:9084 8006:9085 8006:9086 8006:9087 8006:9088 8006:9089 8007:9084 8007:9085 8007:9086 8007:9087 8007:9088 8007:9089 8008:9084 8008:9085 8008:9086 8008:9087 8008:9088 8008:9089 8009:9084 8009:9085 8009:9086 8009:9087 8009:9088 8009:9089 8010:9084 8010:9085 8010:9086 8010:9087 8010:9088 8010:9089 8011:9084 8011:9085 8011:9086 8011:9087 8011:9088 8011:9089 8012:9084 8012:9085 8012:9086 8012:9087 8012:9088 8012:9089 8013:9084 8013:9085 8013:9086 8013:9087 8013:9088 8013:9089 8014:9084 8014:9085 8014:9086 8014:9087 8014:9088 8014:9089 8015:9084 8015:9085 8015:9086 8015:9087 8015:9088 8015:9089 8016:9084 8016:9085 8016:9086 8016:9087 8016:9088 8016:9089 8000:9090 8000:9091 8000:9092 8000:9093 8000:9094 8000:9095 8001:9090 8001:9091 8001:9092 8001:9093 8001:9094 8001:9095 8002:9090 8002:9091 8002:9092 8002:9093 8002:9094 8002:9095 8003:9090 8003:9091 8003:9092 8003:9093 8003:9094 8003:9095 8004:9090 8004:9091 8004:9092 8004:9093 8004:9094 8004:9095 8005:9090 8005:9091 8005:9092 8005:9093 8005:9094 8005:9095 8006:9090 8006:9091 8006:9092 8006:9093 8006:9094 8006:9095 8007:9090 8007:9091 8007:9092 8007:9093 8007:9094 8007:9095 8008:9090 8008:9091 8008:9092 8008:9093 8008:9094 8008:9095 8009:9090 8009:9091 8009:9092 8009:9093 8009:9094 8009:9095 8010:9090 8010:9091 8010:9092 8010:9093 8010:9094 8010:9095 8011:9090 8011:9091 8011:9092 8011:9093 8011:9094 8011:9095 8012:9090 8012:9091 8012:9092 8012:9093 8012:9094 8012:9095 8013:9090 8013:9091 8013:9092 8013:9093 8013:9094 8013:9095 8014:9090 8014:9091 8014:9092 8014:9093 8014:9094 8014:9095 8015:9090 8015:9091 8015:9092 8015:9093 8015:9094 8015:9095 8016:9090 8016:9091 8016:9092 8016:9093 8016:9094 8016:9095 8000:9096 8000:9097 8000:9098 8000:9099 8000:9100 8000:9101 8001:9096 8001:9097 8001:9098 8001:9099 8001:9100 8001:9101 8002:9096 8002:9097 8002:9098 8002:9099 8002:9100 8002:9101 8003:9096 8003:9097 8003:9098 8003:9099 8003:9100 8003:9101 8004:9096 8004:9097 8004:9098 8004:9099 8004:9100 8004:9101 8005:9096 8005:9097 8005:9098 8005:9099 8005:9100 8005:9101 8006:9096 8006:9097 8006:9098 8006:9099 8006:9100 8006:9101 8007:9096 8007:9097 8007:9098 8007:9099 8007:9100 8007:9101 8008:9096 8008:9097 8008:9098 8008:9099 8008:9100 8008:9101 8009:9096 8009:9097 8009:9098 8009:9099 8009:9100 8009:9101 8010:9096 8010:9097 8010:9098 8010:9099 8010:9100 8010:9101 8011:9096 8011:9097 8011:9098 8011:9099 8011:9100 8011:9101 8012:9096 8012:9097 8012:9098 8012:9099 8012:9100 8012:9101 8013:9096 8013:9097 8013:9098 8013:9099 8013:9100 8013:9101 8014:9096 8014:9097 8014:9098 8014:9099 8014:9100 8014:9101 8015:9096 8015:9097 8015:9098 8015:9099 8015:9100 8015:9101 8016:9096 8016:9097 8016:9098 8016:9099 8016:9100 8016:9101 8000:9102 8000:9103 8000:9104 8000:9105 — — 8001:9102 8001:9103 8001:9104 8001:9105 8002:9102 8002:9103 8002:9104 8002:9105 8003:9102 8003:9103 8003:9104 8003:9105 8004:9102 8004:9103 8004:9104 8004:9105 8005:9102 8005:9103 8005:9104 8005:9105 8006:9102 8006:9103 8006:9104 8006:9105 8007:9102 8007:9103 8007:9104 8007:9105 8008:9102 8008:9103 8008:9104 8008:9105 8009:9102 8009:9103 8009:9104 8009:9105 8010:9102 8010:9103 8010:9104 8010:9105 8011:9102 8011:9103 8011:9104 8011:9105 8012:9102 8012:9103 8012:9104 8012:9105 8013:9102 8013:9103 8013:9104 8013:9105 8014:9102 8014:9103 8014:9104 8014:9105 8015:9102 8015:9103 8015:9104 8015:9105 8016:9102 8016:9103 8016:9104 8016:9105

EXAMPLES

Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Example 1 2′-C-Methyl-4′-Fluorouridine 1

To a stirred suspension of 1-1 (20 g, 77.5 mmol), PPh₃ (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of I₂ (25 g, 98.4 mmol) in THF (100 mL) dropwise at 0° C. The mixture was warmed to room temperature (R.T.) and stirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dissolved in a mixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na₂S₂O₃ aq., and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica gel column (0-10% MeOH in DCM) to give 1-2 (22.5 g, 78.9%) as a white solid. ¹H NMR: (DMSO-d₆, 400 MHz) δ 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).

To a stirred solution of 1-2 (24.3 g, 66.03 mmol) in anhydrous MeOH (240 mL) was added NaOMe (10.69 g, 198.09 mmol) at R.T. under N₂. The mixture was refluxed for 3 h. The solvent was removed, and the residue was re-dissolved in anhydrous pyridine (200 mL). To the mixture was added Ac₂O (84.9 g, 833.3 mmol) at 0° C. The mixture was warmed to 60° C. and stirred for 10 h. The solvent was removed, and the residue was diluted with DCM, washed with saturated NaHCO₃ and brine. The organic layer was concentrated and purified on a silica gel column (10-50% EA in PE) to give 1-3 (15 g, 70.1%) as a white solid. ¹H NMR: (CDCl₃, 400 MHz) δ 8.82 (s, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.54 (s, 1H), 5.85 (s, 1H), 5.77 (dd, J=8.0, 2.0 Hz, 1H), 4.69 (d, J=2.4 Hz, 1H), 4.58 (d, J=2.8 Hz, 1H), 2.07 (d, J=5.2 Hz, 6H), 1.45 (s, 3H).

To an ice-cooled solution of 1-3 (15 g, 46.29 mmol) in anhydrous DCM (300 mL) was added AgF (29.39 g, 231.4 mmol). I₂ (23.51 g, 92.58 mmol) in anhydrous DCM (1.0 L) was added dropwise to the solution. The reaction mixture was stirred at R.T. for 5 h. The reaction was quenched with saturated Na₂S₂O₃ and NaHCO₃, and extracted with DCM. The organic layer was separated, dried and evaporated to dryness. The residue was purified on a silica gel column (10-30% EA in PE) to give 1-4 (9.5 g, 43.6%) as a white solid. ¹H NMR: (Methanol-d₄, 400 MHz) δ 7.52 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.73 (d, J=8.0 Hz, 1H), 3.58 (s, 1H), 3.54 (d, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.58 (s, 3H).

To a solution of 1-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (10-30% EA in PE) to give 1-5 (2.8 g, 40.5%). ¹H NMR: (CDCl₃, 400 MHz) δ 8.84 (s, 1H), 8.04-8.06 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.21-7.26 (m, 1H), 6.21 (s, 1H), 5.85 (d, J=18 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.59-4.72 (m, 2H), 2.14 (s, 6H), 1.64 (d, J=6.0 Hz, 3H). ESI-MS: m/z 444.9 [M−F+H]⁺.

A mixture of 1-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept overnight at R. T. in a high-pressure stainless-steel vessel. Ammonia was then evaporated, and the residue purified on silica (50 g column) with a CH₂Cl₂/MeOH solvent mixture (4-12% gradient) to yield compound 1 as a colorless foam (2.0 g; 84% yield). ESI-MS: m/z 275.1 [M−H]⁻.

Example 2 Compound 2

To a solution of 1 (1.2 g; 4.3 mmol) in dioxane (30 mL) were added p-toluenesulphonic acid monohydrate (820 mg; 1 eq.) and trimethyl orthoformate (14 mL; 30 eq.). The mixture was stirred overnight at R.T. The mixture was then neutralized with methanolic ammonia and the solvent evaporated. Purification on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yielded 2-1 (1.18 g, 87%).

To an ice cold solution of 2-1 (0.91 g; 2.9 mmol) in anhydrous THF (20 mL) was added iso-propylmagnesium chloride (2.1 mL; 2 M in THF). The mixture was stirred at 0° C. for 20 mins. A solution of phosphorochloridate reagent (2.2 g; 2.5 eq.) in THF (2 mL) was added dropwise. The mixture was stirred overnight at R.T. The reaction was quenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. The mixture was then diluted with water and CH₂Cl₂, and the two layers were separated. The organic layer was washed with water, half saturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue was purified on silica gel column with CH₂Cl₂-iPrOH solvent system (4-10% gradient) to yield Rp/Sp-mixture of 2-2 (1.59 g; 93%).

A mixture of 2-2 (1.45 g; 2.45 mmol) and 80% aq. HCOOH (7 mL) was stirred at R.T. for 1.5 h. The solvent was evaporated and coevaporated with toluene. The obtained residue was dissolved in MeOH, treated with Et₃N (3 drops) and the solvent was evaporated. Purification on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yielded Rp/Sp-mixture of compound 2 (950 mg; 70%). ³¹P-NMR (DMSO-d₆): δ 3.52, 3.47. MS: m/z=544 [M−1]⁻.

Example 3 Compound 3

To an ice cold solution of 3-1 (80 mg; 015 mmol) in anhydrous THF (2 mL) was added isopropylmagnesium chloride (0.22 mL; 2 M in THF). The mixture was stirred at 0° C. for 20 mins. A solution of the phosphorochloridate reagent (0.16 g; 0.45 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred overnight at R.T. The reaction was quenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. The mixture was diluted with water and CH₂Cl₂, and the two layers were separated. The organic layer was washed with water, half saturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue was purified on silica gel column with CH₂Cl₂-MeOH solvent system (2-10% gradient) to yield Rp/Sp-mixture of 3-2 (102 mg; 80%).

A mixture of 3-2 (100 mg; 0.12 mmol) in EtOH (3 mL) and 10% Pd/C (10 mg) was stirred under the H₂ atmosphere for 1.5 h. The mixture was filtered through a Celite pad, evaporated and purified on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) to yield Rp/Sp-mixture of compound 3 (52 mg, 74%). ³¹P-NMR (DMSO-d₆): δ 3.51, 3.48. MS: m/z=584 [M−1]⁻.

Example 4 Compounds 4 and 6

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750 mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15 mins at bath temperature 42° C., and then cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃ (0.009 mL, 0.1 mmol). The mixture was kept at R.T. for 45 mins. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate (100 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In 1 h, the reaction was quenched with 2M ammonium acetate buffer (1 mL, pH=7.5), diluted water (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose High Performance. The separation was done in linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions eluted at 60% buffer B contained Compound 4 and at 80% buffer B contained Compound 6. The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Compound 4: ³¹P-NMR (D₂O): −3.76 (s); MS: m/z 355.3 [M−H]⁻. Compound 6: ³¹P-NMR (D₂0): −9.28 (d, 1H, Pα), −12.31 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS: m/z 515.0 [M−1]⁻.

Example 5 Compound 5

Compound 5 was synthesized as described for 2 on 0.1 mmol scale and with neopentyl ester of phosphorochloridate reagent. Yield was 36 mg (63%). ³¹P-NMR (CDCl₃): δ 2.57 (s), 2.43 (s). MS: 572.6 [M−1]⁻.

Example 6 Compound 7

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750 mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15 mins at bath temperature 42° C., and then cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by PSCl₃ (0.01 mL, 0.1 mmol). The mixture was kept at R.T. for 1 h. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate (200 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In 2 h, the reaction was quenched with 2M ammonium acetate buffer (1 mL, pH=7.5), diluted with water (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose High Performance. Separation was done in linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions eluted at 80% buffer B contained 7 (compounds 7a and 7b). The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 20% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. Two peaks were collected. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Peak 1 (more polar): ³¹P-NMR (D₂O): +42.68 (d, 1H, Pα), −9.05 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS 530.90 [M−1]⁻. Peak 2 (less polar): ³¹P-NMR (D₂O): +42.78 (d, 1H, Pα), −10.12 (bs, 1H, Pγ), −23.94 (t, 1H, Pβ); and MS 530.90 [M−1]⁻.

Example 7 Compound 23

To a stirred suspension of 23-1 (20.0 g, 81.3 mmol), imidazole (15.9 g, 234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrous THF (100 mL) was added a solution of I₂ (41.3 g, 162.6 mmol) in THF (150 mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirred for 14 h. The reaction was quenched with sat. aq. Na₂S₂O₃ (150 mL) and extracted with THF/EA (1/1) (100 mL×3). The organic layer was dried over Na₂SO₄, and concentrated at a low pressure. The residue was recrystallized from EtOH to afford pure 23-2 (23 g, 79%) as a white solid.

To a stirred solution of 23-2 (23 g, 65 mmol) in anhydrous MeOH (200 mL) was added NaOCH₃ (10.5 g, 195 mmol) in MeOH (50 mL) at R.T. The mixture was stirred at 60° C. for 3 h, and quenched with dry ice. A solid precipitated and removed by filtration. The filtrate was concentrated at a low pressure. The residue was purified on column silica gel column (MeOH in DCM from 1% to 10%) to provide 23-3 (13.1 g, 92.5%) as a white foam solid.

To a stirred solution of 23-3 (12.0 g, 53 mmol) in anhydrous CH₃CN was added TEA.3HF (8.5 g, 53 mmol) and NIS (10.2 g, 63.6 mmol) at 0° C. The mixture was stirred for 30 mins, and slowly warmed to R.T. The mixture was stirred for another 30 mins. The solid was removed by filtration, and washed with DCM to give 23-4 (14 g, 73%) as a yellow solid. ESI-MS: m/z 373.0 [M+H]⁺.

To a stirred solution of 23-4 (12.0 g, 32 mmol) and DMAP (1.2 g, 9.6 mmol) in pyridine (100 mL) was added Bz₂O (21.7 g, 96 mmol) at R.T. The mixture was stirred at 50° C. for 16 h. The resulting solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified on silica gel column (50% EA in PE) to give 23-5 (15 g, 81%) as a white solid. ESI-TOF-MS: m/z 581.0 [M+H]⁺.

Tetra-butylammonium hydroxide (288 mL as 54-56% aqueous solution, 576 mmol) was adjusted to pH˜4 by adding TFA (48 mL). The resulting solution was treated with a solution of 23-5 (14 g, 24 mmol) in DCM (200 mL). m-Chloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portion wise with vigorous stirring, and the mixture was stirred overnight. The organic layer was separated and washed with brine. The resulting solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 23-6 (7.5 g, 68%)

Compound 23-6 (5.0 g, 10.6 mmol) was treated with 7N NH₃.MeOH (100 mL), and the mixture was stirred for 5 h. The mixture was then concentrated to dryness at low pressure. The residue was washed with DCM, and the solid was filtered to give 23-7 (2.1 g, 75%) as a white foam. ESI-MS: m/z 263.0 [M+H]⁺.

To a solution of 23-7 (2.1 g, 8.0 mmol) in pyridine was added TIDPSCl (2.5 g, 8.0 mmol) dropwise at 0° C., and stirred for 12 h. at R.T. The solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified by column chromatography (EA in PE from 10% to 50%) to give pure 23-8 (1.6 g, 40%) as a white foam.

A solution of 23-8 (1.5 g, 3.0 mmol) and IBX (1.69 g, 6.0 mmol) in anhydrous CH₃CN (10 mL) was stirred at 80° C. for 3 h. The mixture was cooled down to R.T. and filtered. The filtrate was concentrated to dryness at low pressure. The residue was purified by column chromatography (EA in PE from 2% to 50%) to give pure 23-9 (1.2 g, 80%) as a white foam. ESI-MS: m/z 503.0 [M+H]⁺

Compound 23-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Ethynyl magnesium bromide (8 mL of 0.5M solution in cyclohexane) was added at R.T. After 30 mins, additional ethynyl magnesium bromide (8 mL) was added. The mixture was left for 30 mins, and then quenched with sat. solution of ammonium chloride. The product was extracted with EA. The organic extracts were washed with brine, dried, and concentrated. The residue was purified by flash chromatography on silica gel in EA to remove the dark color. The yellow compound was dissolved in THF (3 mL) and treated with TBAF (1 mL, 2M solution in THF) for 30 mins. The solvent was evaporated, and the residue was subjected to silica gel chromatography on a Biotage cartridge (25 g). EA saturated with water was used for isocratic elution. Each fractions were analyzed by TLC in DCM-MeOH (9:1 v/v). Fractions containing only the isomer with a high Rf were concentrated to give pure compound 23 (110 mg). MS: 285.1 [M−1]⁻.

Example 8 Compound 22

Compound 23 (57 mg, 0.2 mmol) was dissolved in CH₃CN (2 mL), containing N-methylimidazole (40 uL). The phosphorochloridate (207 mg, 0.6 mmol) was added, and the mixture was kept overnight at 40° C. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The product was isolated by silica gel chromatography in gradient of methanol in DCM from 0% to 15%. Compound 22 was obtained (46 mg, 39%). MS: m/z 593.9 [M−1]⁻.

Example 9 Compound 51

To a solution of triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.74 mmol) in THF was added 51-1 (0.16 gg; 0.49 mmol). The mixture evaporated and rendered anhydrous by coevaporating with pyridine follow by toluene. The residue was dissolved in anhydrous THF and cooled in an ice-bath. Diisopropylethyl amine (0.34 mL) was added, followed by BOP-Cl (250 mg) and 3-nitro-1,2,4-triazole (112 mg) in THF (5 mL). The mixture was stirred at 0° C. for 90 mins, diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). The residue was purified on silica column with 3-10% i-PrOH in DCM to give 51-2 (0.2 g, 64%).

A solution of 51-2 (0.20 g; 0.31 mmol) in 80% aq. HCOOH was stirred at R.T. for 2 h, and then concentrated. The residue was coevaporated with toluene and then with MeOH containing a small amount of Et₃N (2 drops). Purification on silica gel (10 g column) with CH₂Cl₂/MeOH (4-10% gradient) was followed by RP-HPLC purification in 5 runs on a Synergi Hydro RP column 250×30 mm (Phenomenex P/N 00G-4375-U0-AX) using H₂O and ACN both 50 mM TEAA. The Gradient was 25-75% ACN in 20 mins at 24 mL/mins, 254 nM detection. The compound eluted at 16.0 minutes; and the pure fractions were pooled and lyophilized. TEAA was removed by dissolving the compound in DMSO (2 mL) and using the same column and same gradient, using only H₂O and ACN. Pure fractions were pooled and lyophilized to give compound 51 (18 mg). MS: m/z=1197 [2M+1]⁺.

Example 10 Compound 8

Compound 8-1 (5.0 g, 8.5 mmol) and 2-amino-6-chloropurine (3.0 g, 17.7 mmol) were co-concentrated with anhydrous toluene for 3 times. To a stirred suspension of the above mixtures in anhydrous MeCN (50 mL) was added DBU (7.5 g, 49 mmol) at 0° C. The mixture was stirred at 0° C. for 15 mins, and then TMSOTf (15 g, 67.6 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 15 mins. The mixture was heated at 70° C. overnight. The mixture was cooled to R.T., and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified by column on silica gel (PE/EA: from 15/1 to 3/1) to give 8-2 (2.5 g, 46.3%) as a white foam.

To a solution of 8-2 (10 g, 15.7 mmol), AgNO₃ (8.0 g, 47 mmol) and collidine (10 mL) in anhydrous DCM (20 mL) was added MMTrCl (14.5 g, 47 mmol) in small portions under N₂. The mixture was stirred at R.T. overnight. The mixture was filtered, and the filtrate was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/ME=20/1 to 8/1) to give 8-3 (10 g, 70%) as a yellow solid.

To a solution of 3-hydroxy-propionitrile (3.51 g, 49.4 mmol) in anhydrous THF (100 mL) was added NaH (2.8 g, 70 mmol) at 0° C., and the mixture was stirred at R.T. for 30 mins. A solution of 8-3 (8.5 g, 9.35 mmol) in anhydrous THF (100 mL) at 0° C. was added, and the mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 20/1) to give 8-4 (4.5 g, 83%) as a white solid.

Compound 8-4 (1.5 g, 2.6 mmol) was co-concentrated with anhydrous pyridine 3 times. To an ice-cooled solution of 8-4 in anhydrous pyridine (30 mL) was added TsCl (1.086 g, 5.7 mmol), and the mixture was stirred at 0° C. for 1 h. The reaction was quenched with water, and extracted with EA (80 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 15/1) to give 8-5 (1.4 g, 73%) as a white solid.

To a solution of 8-5 (4.22 g, 5.7 mmol) in acetone (60 mL) was added NaI (3.45 g, 23 mmol), and the mixture was refluxed overnight. The reaction was quenched with sat. aq. Na₂S₂O₃ and extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 15/1) to give 8-6 (4 g, 73%) as a white solid.

To a solution of 8-6 (4.0 g, 5.8 mmol) in anhydrous THF (60 mL) was added DBU (3.67 g, 24 mmol), and the mixture was stirred at 60° C. overnight. The mixture was diluted with EA (80 mL), and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 20/1) to give 8-7 (2 g, 61%) as a white solid.

To an ice-cooled solution of 8-7 (500 mg, 0.89 mmol) in anhydrous DCM (20 mL) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97 mmol) in anhydrous DCM (20 mL). The mixture was stirred at R.T. for 3 h. The reaction was quenched with sat Na₂S₂O₃ and NaHCO₃ aqueous, and the mixture was extracted with DCM (50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated to give the crude 8-8 (250 mg) as a yellow solid.

To a solution of crude 8-8 (900 mg, 1.28 mmol) in anhydrous DCM (50 mL) was added DMAP (1.0 g, 8.2 mmol) and BzCl (795 mg, 5.66 mmol). The mixture was stirred at R.T. overnight. The mixture was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by prep-TLC (DCM/MeOH=15:1) to give 8-9 (300 mg, 26%) as a white solid.

To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). The mixture was stirred at 60° C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1:1) to give crude 8-10 (550 mg, 73%) as a white solid.

The crude 8-10 (550 mg, 0.6 mmol) was dissolved in NH₃/MeOH (7N, 50 mL). The mixture was stirred at R.T. overnight. The mixture was concentrated, and the residue was purified by silica gel column (DCM/MeOH from 100/1 to 20/1) to give 8-11 (62 mg, 17%) as a white solid. ESI-MS: m/z 598.0 [M+H]⁺

A solution of 8-11 (12 mg) in 80% formic acid (0.5 mL) stood at R.T. for 3.5 h and then was concentrated. The residue was co-evaporated with MeOH/toluene 4 times in a vial, and triturated with EtOAc at 40° C. The EtOAc solution removed with pippet. The trituration step was repeated several times, and the remaining solid was dissolved in MeOH. The solution was concentrated and dried to give compound 8 as off white solid (4.7 mg). ESI-MS: m/z 326.6 [M+H]⁺.

Example 11 Compounds 34 and 35

To a stirred suspension of 8-1 (50 g, 84.8 mmol) and 2-amino-6-chloropurine (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL) was added DBU (77.8 g, 508 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0° C. The mixture was stirred at R.T. for 20 mins until a clear solution was formed. The mixture was stirred at 90-110° C. overnight. The mixture was cooled to R.T., and diluted with EA. The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and then concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give 34-1 (30 g, 55.5%) as a white solid.

To a solution of 34-1 (30 g, 47.1 mmol) in anhydrous DCM (300 mL) was added collidine (30 mL), AgNO₃ (24 g, 141.4 mmol) and MMTrCl (43.6 g, 141.4 mmol). The mixture was stirred at R.T. overnight. The mixture was filtered, and the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=4/1) to give 34-2 (35 g, 82%) as a white solid.

To a stirred solution of 34-2 (35 g, 38.5 mmol) in anhydrous EtOH (150 mL) was added a solution of EtONa in EtOH (2N, 150 mL). The mixture was stirred at R.T. overnight, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and the solution was washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/2) to give 34-3 (19 g, 81%) as a white solid.

Compound 34-3 (19 g, 31.3 mmol) was co-concentrated with anhydrous pyridine for 3 times. To an ice-cooled solution of 34-3 in anhydrous pyridine (120 mL) was added a solution of TsCl (6.6 g, 34.6 mmol) in pyridine (40 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 16 h. The mixture was quenched with water, and the reaction mixture was concentrated. The residue was re-dissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (DCM/MeOH=100/1) to give 34-4 (16 g, 67%) as a yellow solid.

To a solution of 34-4 (15 g, 19.7 mmol) in acetone (100 mL) was added NaI (30 g, 197 mmol). The mixture was refluxed overnight, and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1) to give 34-5 (9 g, 63.7%) as a white solid.

To a solution of 34-5 (8 g, 11.2 mmol) in anhydrous THF (60 mL) was added DBU (5.12 g, 33.5 mmol), and the mixture was heated at 60° C. overnight. The mixture was diluted with EA, and washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE/acetone=4/1) to give 34-6 (5.7 g, 86%) as a white solid. ¹H-NMR (CD₃OH, 400 MHz) δ=8.18 (s, 1H), 7.17-7.33 (m, 12H), 6.80 (d, J=8.8 Hz, 2H), 5.98 (s, 1H), 5.40 (d, J=8.6 Hz, 1H), 3.87 (m, 5H), 3.75 (s, 3H), 2.69 (s, 1H), 1.05 (s, 3H).

To an ice-cooled solution of 34-6 (4.44 g, 7.5 mmol) in anhydrous MeCN (45 mL) was added TEA.3HF (1.23 g, 7.6 mmol) and NIS (2.16 g, 9.5 mmol). The mixture was stirred at R.T. for 2-3 h. The reaction was quenched with sat. Na₂SO₃ and NaHCO₃ solution. The mixture was extracted with EA (3×100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone=100/2) to give 34-7 (4.4 g, 79.8%) as a white solid.

To a solution of 34-7 (5.36 g, 7.3 mmol) in anhydrous DCM (50 mL) was added DMAP (3.6 g, 29.8 mmol) and BzCl (3.1 g, 22.1 mmol) at 0° C. The mixture was stirred at R.T. overnight. The mixture was washed with sat. aq. NaHCO₃ and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 34-8 (5.6 g, 81.3%) as a white solid.

To a solution of 34-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100° C. for 48 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 34-9 (3.9 g, 78.5%) as a white solid.

Compound 34-9 in NH₃ in MeOH (7N, 60 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone=50/1) to give 34-10 (500 mg, 74.7%) as a white solid. ESI-MS: m/z 626.3 [M+H]⁺.

To a solution of 34-10 (350 mg, 0.56 mmol) in anhydrous pyridine (4 mL) was added imidazole (50 mg, 0.72 mmol) and TBSCl (108 mg, 0.72 mmol) at 0 to 5° C., and stirred at R.T. for 15 h. The reaction was quenched with absolute EtOH (0.5 mL). The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (150 mL), and washed with water, sat. NaHCO₃ and brine. The combined organic layers were dried over Na₂SO₄, filtered and evaporated at low pressure. The residue was purified by silica gel column (10-30% EA in hexanes) to give 34-11 (338 mg, 81.8%) as a white solid.

To a solution of compound 34-11 (328 mg, 0.44 mmol), AgNO₃ (226 mg, 1.33 mmol) and collidine (0.59 mL, 4.84 mmol) in anhydrous DCM (4 mL) was added MMTrCl (410 mg, 1.33 mmol) under N₂. The mixture was stirred at R.T. overnight under N₂, and monitored by TLC to completion. The mixture was filtered through pre-packed Celite filter, and the filtrate was washed with water, 50% aqueous citric acid, and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (EA in hexanes from 0% to 30%) to give 34-12 (337 mg).

To a solution of 34-12 (337 mg, 0.33 mmol) in anhydrous THF (4 mL) was added 1.0 M solution of TBAF (0.66 ML, 0.66 mmol) at 0 to 5° C. The reaction was slowly warmed to R.T., and stirred for 1 h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to give the crude product, which was purified by silica gel column (EA in hexanes from 0% to 50%) to give 34-13 (188 mg).

To a stirred solution of 34-13 (180 mg, 0.16 mmol) in anhydrous CH₃CN (2.5 mL) was added N-methylimidazole (132 μL, 1.6 mmol) at 0-5° C. (ice/water bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (207 mg, 0.6 mmol, dissolved in 2 mL of CH₃CN). The solution was stirred at R.T. for 2.5 h, and the mixture was diluted with EA followed by addition of water (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give 34-14 (75.8 mg) and 34-15 (108 mg) as a slower eluting isomer.

Compound 34-14 (76 mg, 0.063 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (47 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile and water, and lyophilized to give compound 34 (26.6 mg). ESI-LCMS: m/z=663.3 [M+H]⁺.

Compound 34-15 (108 mg, 0.089 mmol) was dissolved in anhydrous CH₃CN (0.7 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 60 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile and water, and lyophilized to give compound 35 (40.3 mg). ESI-LCMS: m/z=663.2 [M+H]⁺.

Example 12 Compound 25

To a solution of 25-1 (260 mg, 1 mmol), PPh₃ (780 mg, 3 mmol) and pyridine (0.5 mL) in anhydrous THF (8 mL) were added I₂ (504 mg, 2 mmol) at R.T., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with EtOAc and washed with 1M HCl solution. The organic layer was dried over Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 25-2 (190 mg, 85%) as a white solid.

To a solution of 25-2 (190 mg, 0.52 mmol) in THF (4 mL) was added DBU (760 mg, 5 mmol) at R.T., and the mixture was heated at 50° C. overnight. The mixture was diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-3 (75 mg, 52%) as a white solid.

To a solution of 25-3 (200 mg, 0.82 mmol) in MeCN (anhydrous, 4 mL) was added NIS (337 mg, 1.5 mmol) and TEA.3HF (213 mg, 1.25 mmol) at R.T., and the mixture was stirred at R.T. for 7 h. The reaction was quenched with sat. Na₂SO₃ solution and sat. aq. NaHCO₃ solution. The mixture was extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 25-4 (300 mg, 62%) as a white solid.

To a solution of 25-4 (194 mg, 0.5 mmol) in pyridine (5 mL) was added BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5 h, and the reaction was quenched with water. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 25-5 (397 mg, 81%) as a white solid.

To a solution of 25-5 (1.05 g, 2.13 mmol) in DCM (12 mL) was added a mixture of TFA (0.5 mL) and Bu₄NOH (1 mL), followed by addition of m-CPBA (1.3 g, 6 mmol) at R.T. The mixture was stirred at R.T. for 5 h. The mixture was washed with sat. Na₂SO₃ solution and aq. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-6 (450 mg, 63%) as a white solid.

Compound 25-6 (250 mg, 0.65 mmol) was dissolved in NH₃/MeOH (5 mL). The mixture was stirred at R.T. for 5 h, and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give compound 25 (120 mg, 66%) as a white powder. ESI-MS: m/z 279.0 [M+H]⁺.

Example 13 Compound 31

To a stirred solution of compound 25 (100 mg, 0.36 mmol) in anhydrous THF (3.0 mL) was added N-methylimidazole (236 μL, 2.87 mmol) at 0° C. (dry ice/acetone bath) followed by a solution of the phosphorochloridate (329 mg, 1.08 mmol, dissolved in 2 mL of THF). The solution was stirred at 0° C. for 1 h, the reaction temperature was raised up-to 10° C. during the next 1 h, and the solution was left at 10° C. for the next 4 h. The mixture was cooled to 0 to 5° C., diluted with EA, and water was added (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CH₃CN/H₂O. The residue was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give a mixture of two isomers of compound 31 (17.5 mg). MS: m/z 546.05 [M−H]⁻.

Example 14 Compound 27

To a solution of compound 25 (139 mg, 0.5 mmol) in pyridine (5 mL) was added BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5 h, diluted with EtOAc and washed with 1N HCl solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 27-1 (274 mg, 79%) as a white solid.

To a solution of 27-1 (490 mg, 1 mmol), DMAP (244 mg, 2 mmol) and TEA (205 mg, 2.1 mmol) in MeCN (10 mL) were added TPSCl (604 mg, 2 mmol) at 0° C. The mixture was stirred at R.T. for 2 h., and then NH₄OH aq. was added at R.T. The mixture was stirred for 0.5 h, diluted with EtOAc and washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 27-2 (250 mg, 41%) as a white solid.

Compound 27-2 (250 mg, 0.51 mmol) was dissolved in NH₃/MeOH (15 mL). The mixture was stirred at R.T. for 5 h. and then concentrated at low pressure. The residue was purified by silica gel column (5% DCM in DCM) to give compound 27 (95 mg, 66%) as a white powder. ESI-MS: m/z 278.1 [M+H]⁺.

Example 15 Compound 29

To a solution of compound 29-1 (30 g, 0.08 mol) in anhydrous THF (300 mL) was added a solution of lithium tri-tert-butoxyaluminohydride (120 mL, 0.12 mol) dropwise at −78° C. under N₂. The mixture was stirred at −20° C. for 1 h. The reaction was quenched with sat. aq. NH₄Cl and then filtered. The filtrate was extracted with EA (3×300 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 29-2 (26 g, 86%) as a colorless oil.

To a stirred solution of PPh₃ (37.7 g, 0.144 mol) in DCM (100 mL) was added compound 29-2 (27 g, 0.072 mol) at −20° C. under N₂. After the mixture was stirred at R.T. for 15 mins, CBr₄ (42 g, 0.129 mol) was added while maintaining the reaction temperature between −25 and −20° C. under N₂. The mixture was then stirred below −17° C. for 20 mins. Silica gel was added into the solution, and then purified by flash silica gel column separation to give the crude oil product. The crude was purified by silica gel column (EA in PE from 2% to 20%) to give 29-3 (α-isomer, 17 g, 55%) as a colorless oil.

A mixture of 6-Cl-guanine (11.6 g, 68.8 mmol) and t-BuOK (8.2 g, 73 mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stirred at 35° C. for 30 mins, and then 29-3 (10 g, 22.9 mmol) in MeCN 100 mL) was added at R.T. The mixture was heated at 50° C. overnight. The reaction was quenched with a solution of NH₄Cl (5 g) in water (40 mL), and the mixture was filtered. The filtrate was evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-4 (6 g, 42%) as a yellow solid.

To a solution of 29-4 (12.5 g, 23.8 mol) in DCM (50 mL) was added AgNO₃ (8.1 g, 47.6 mmol), collidine (5.77 g, 47.6 mmol) and MMTrCl (11 g, 35.7 mmol). The mixture was stirred at R.T. overnight. The reaction was quenched with MeOH (5 mL), filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give the intermediate (16 g, 86%) as a yellow solid. To a solution of HOCH₂CH₂CN (4.7 g, 66 mmol) in THF (200 mL) was added NaH (3.7 g, 92 mmol) at 0° C. The mixture was stirred at R.T. for 30 mins. A solution of the intermediate (10.5 g, 13 mmol) in THF (50 mL) was added, and the reaction mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (2 mL), diluted with EA (100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 29-5 (5.8 g, 77%) as a yellow solid.

To a solution of PPh₃ (7.0 g, 26.6 mmol) in anhydrous pyridine (100 mL) was added I₂ (6.3 g, 24.9 mmol), and stirred at R.T. for 30 mins. The mixture was treated with a solution of 29-5 (9.5 g, 16.6 mmol) in pyridine (40 mL). The mixture was stirred at R.T. overnight. The reaction was quenched with sat. Na₂S₂O₃ solution, and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-6 (7 g, 66%) as a yellow solid.

To a solution of 29-6 (7.5 g, 11 mmol) in dry THF (50 mL) was added DBU (5.4 g, 33 mmol), and the mixture was heated to reflux for 4 h. The mixture was diluted with EA (3×100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-7 (4.0 g, 67%) as a white solid.

To an ice-cooled solution of 29-7 (3.0 g, 5.4 mmol) in anhydrous MeCN (20 mL) was added TEA.3HF (0.65 g, 4.1 mmol) and NIS (1.53 g, 6.78 mmol) at R.T., and the reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with EA (50 mL), and washed with sat. Na₂S₂O₃ solution and NaHCO₃ aq. The organic layer was dried over anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to separate the two isomers (about 1:1). NOE showed the polar one was 29-8 (0.6 g, 16%) as a white solid.

To a solution of 29-8 (0.7 g, 1 mmol) in dry pyridine (10 mL) was added BzCl (147 mg, 1.05 mmol) at 0° C. The mixture was stirred at R.T. for 3 h. The mixture was then diluted with EA, and washed with sat. NaHCO₃ aq. and brine. The organic layer was dried over Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-9 (0.65 g, 81%) as a white solid.

To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mL), and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-10 (500 mg, 78%) as a white solid.

Compound 29-10 (400 mg, 0.5 mmol) in NH₃/MeOH (7N, 100 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 29-11 (220 mg, 63%) as a white solid. ESI-MS: m/z 590.3 [M+H]⁺.

Compound 29-11 (59 mg, 0.1 mmol) was dissolved in 50% TFA in methanol (10 mL), and the mixture was kept at R.T. for 2 h. The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of the acid. The residue was suspended in CH₃CN (1 mL) and centrifuged. The precipitate was washed with CH₃CN (1 mL) and dried. Compound 29 was obtained as a colorless solid (21 mg, 65%. MS: m/z 316.2 [M−1]⁻.

Example 16 Compounds 42 and 43

A freshly prepared EtONa in dry EtOH (2N, 150 mL) was added to a solution of 29-4 (13.67 g, 17.15 mmol) in EtOH (50 mL) at 0° C. The mixture was stirred at R.T. for 1 h, and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 42-1 (10 g, 98%) as a yellow solid.

To a solution of PPh₃ (2.73 g, 10.4 mol) in anhydrous pyridine (60 mL) was added I₂ (2.48 g, 9.76 mmol) at R.T., and the reaction mixture was stirred R.T. for 30 mins. A solution of 42-1 (3.9 g, 6.51 mmol) in pyridine (10 mL) was added. The mixture was stirred at R.T. overnight. The reaction was quenched with sat. Na₂S₂O₃ solution and NaHCO₃ aq., and then extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (2% MeOH in DCM) to give 42-2 (3.0 g, 75%) as a yellowed solid.

To a solution of 42-2 in dry THF (300 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to reflux for 3 h. The mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-3 (0.6 g, 37.5%) as a white solid.

To an ice-cooled solution of 42-3 (2.0 g, 3.44 mmol) in anhydrous MeCN (20 mL) was added NIS (0.975 g, 4.3 mmol) and TEA.3HF (0.82 g, 5.16 mmol) at 0° C. The mixture was stirred at R.T. for 2 h. The reaction was quenched with sat. Na₂SO₃ and NaHCO₃ aqueous solution, and then concentrated at low pressure. The residue was dissolved in EA (50 mL), washed with brine, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-4 (1.5 g, 60%) as a white solid.

To a solution of 42-4 (1 g, 1.37 mmol) in dry pyridine (100 mL) was added BzCl (0.23 g, 1.65 mmol) at 0° C. The reaction was stirred for 30 mins and checked by LCMS. The mixture was concentrated at low pressure, and the residue was dissolved in EA (50 mL). The solution was washed with brine. The organic layer was dried over MgSO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (10% EA in PE) to give 42-5 (0.9 g, 78%) as a white solid.

To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100 mL), and washed with water and brine. The organic phase was dried over MgSO₄, and concentrated at low pressure. The residue was purified by silica gel column (15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid.

Compound 42-6 (1.35 g, 1.64 mmol) in NH₃/MeOH (150 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 42-7 (0.9 g, 90%) as a white solid. ESI-MS: m/z 618.3 [M+H]⁺.

To a solution of 42-7 (99 mg, 0.16 mmol) in DCM (1.0 mL), triethylamine (92.7 μL, 0.64 mmol) was added at R.T. The mixture was cooled to 0 to 5° C. (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (36.6 μL, 0.2 mmol, prepared according to a procedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added to the mixture. The mixture was stirred 0 to 5° C. (ice/water bath) for 15 mins, followed by addition of N-methylimidazole (26.3 μL, 0.32 mmol). The mixture was then stirred for 1 h at 0 to 5° C. TLC showed absence of 42-7. EA (100 mL) was added, followed by water. The organic layer was washed H₂O, saturated aqueous NH₄Cl solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 10% iPrOH/DCM to give a mixture of 42-a and 42-b (61.5 mg).

A mixture of 42-a and 42-b (61.5 mg, 0.085 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (64 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 42 (1.8 mg) and compound 43 (14.5 mg).

Compound 42: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 8.0 (s, 1H), 6.69 (d, J=16.0 Hz, 1H), 5.9-5.6 (br s, 1H), 4.94-4.85 (m, 1H), 4.68-4.52 (m, 3H), 1.49-1.3 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.8 (s), −160.06 (s); ³¹P NMR (CD₃OD-d₄) δ −7.97 (s). ESI-LCMS: m/z=450.1 [M+H]⁺; Compound 43: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.96 (s, 1H), 6.68 (s, 1H), 6.69 (d, J=16.8 Hz, 1H), 6.28-6.1 (br s, 1H), 4.81-4.5 (m, 4H), 1.45-1.39 (m, 12H); ³¹P NMR (CD₃OD-d₄) δ −5.84 (s). ESI-LCMS: m/z=450.0 [M+H]⁺.

Example 17 Compounds 32 and 33

To a solution of 42-7 (0.47 g, 0.65 mol) in DCM (3 mL) was added AgNO₃ (0.22 g, 1.29 mmol), collidine (0.15 g, 1.29 mmol) and MMTrCl (0.3 g, 0.974 mmol) at 0° C. The mixture was stirred at R.T. overnight. The mixture was filtered, and the filter was washed with sat. aq. NaHCO₃ solution and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column to give 32-1 (0.55, 85%) as a white solid.

To a solution of 32-1 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO₄ and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 32-2 (0.3 g, 60%) as a white solid.

Compound 32-2 (0.3 g, 0.3 mmol) in NH₃/MeOH (30 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 32-3 (145 mg, 56%) as a white solid. ESI-LCMS: m/z 890.5 [M+H]⁺.

To a stirred solution of 32-3 (161 mg, 0.16 mmol) in anhydrous CH₃CN (2.0 mL) was added N-methylimidazole (118 μL, 2.87 mmol) at 0 to 5° C. (ice/water bath) followed by solution of 32-4 (186 mg, 0.54 mmol, dissolved in 2 mL of CH₃CN). The solution was stirred at 0 to 5° C. for 4 h. The mixture was diluted with EA, and water was added (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give as 32-5 (82.6 mg) as the faster eluting isomer and 32-6 (106 mg) as the slower eluting isomer.

Compound 32-5 (82.6 mg, 0.07 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (35 μL) was added at 0 to 5° C. The mixture was stirred at R.T. for 1 h, and anhydrous EtOH (100 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, and purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 32 (19.4 mg). ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.9 (s, 1H), 7.32-7.28 (t, J=8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d, J=17.6 Hz, 1H), 4.70-4.63 (m, 2H), 4.55-4.4 (m, 3H), 3.94-3.9 (m, 1H), 1.79-1.67 (m, 4H), 1.53-1.49 (m, 1H), 1.45-1.22 (m, 15H); ³¹P NMR (CD₃OD-d₄) δ4.06 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.15 [M−H]⁻.

Compound 32-6 (100 mg, 0.083 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (50 μL) was added at 0 to 5° C. Following the procedure for obtaining compound 32, compound 33 (31.8 mg) was obtained. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H), 7.33-7.29 (m, 2H), 7.24-7.14 (m, 3H), 6.41 (d, J=17.6 Hz, 1H), 4.70-4.60 (m, 2H), 4.54-4.49 (m, 2H), 4.44-4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 1.54-1.24 (m, 16H); ³¹P NMR (CD₃OD-d₄) δ 3.91 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.1 [M−H]⁻.

Example 18 Compound 53

Compound 53-1 (70 mg, 58%) was prepared from 32-3 (90 mg; 0.1 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.2 mmol) with DIPEA (87 μL), BopCl (44 mg), and 3-nitro-1,2,4-triazole (29 mg) in THF (2 mL) according to a method described for compound 51-2. Purification was done with hexanes/EtOAc solvent system, 20-80% gradient.

Compound 53 (25 mg, 64%) was prepared from 53-1 (70 mg) in acetonitrile (0.6 mL) and 4 N HCl/dioxane (50 μL) according to a method described for compound 51. MS: m/z=658 [M+1]⁺.

Example 19 Compounds 40 and 41

To a mixture of pre-silylated 6-Cl-guanine (using HMDS and (NH₄)₂SO₄) (25.2 g, 150 mmol) in DCE (300 mL) was added 40-1 (50 g, 100 mmol) and TMSOTf (33.3 g, 150 mmol) at 0° C. The mixture was stirred at 70° C. for 16 h, and then concentrated at low pressure. The residue was re-dissolved in EA, and washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified on silica gel column (PE/EA=2/1) to give pure 40-2 (45 g, 73%) as a white solid.

To a solution of 40-2 (45 g, 73.4 mmol) in EtOH (73 mL) was added with EtONa (1N in EtOH, 360 mL). The mixture was stirred at R.T. for 16 h. The mixture was then concentrated to give a residue, which was purified by silica gel column (DCM/MeOH=10/1) to give pure 40-3 (19 g, 83%) as a white solid.

To a solution of 40-3 (19 g, 61.1 mmol) in pyridine (120 mL) was added with TIPDSCl₂ (19.2 g, 61 mmol) dropwise at 0° C. The mixture was stirred at R.T. for 16 h, and then concentrated at low pressure. The residue was re-dissolved in EA, and washed with sat. aq. NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=20/1) to give pure 40-4 (22 g, 65%) as a white solid.

To a solution of 40-4 (22 g, 39.8 mmol) in DMF/pyridine (5/1, 100 mL) was added TMSCl (12.9 g, 119 mmol) dropwise at 0° C. The mixture was stirred at R.T. for 1 h and then treated with isobutyryl chloride (5.4 g, 50 mmol). The mixture was stirred at R.T. for 3 h and then quenched by NH₄OH. The mixture was concentrated at low pressure. The residue was dissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃, and then the organic layer was dried and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=50/1) to give pure 40-5 (15 g, 60%) as a white solid.

To a solution of 40-5 (15 g, 24.1 mmol) in DCM (100 mL) was added PDC (13.5 g, 26 mmol) and Ac₂O (9.8 g, 96 mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reaction was quenched by sat. aq. NaHCO₃, and then extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was dissolved in anhydrous THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF (200 mL) was added n-BuLi (2.5 N, 44 mL) at −78° C. The mixture was stirred at −78° C. for 15 mins and 0° C. for 15 mins. The mixture was treated with a solution of crude ketone in THF at −78° C. and stirred at −30° C. for 2 h. The reaction was quenched by sat. aq. NH₄Cl, and then extracted by EA. The combined organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give pure 40-6 (3.1 g, 18%) as a white solid.

To a solution of 40-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) in DCM (35 mL) was added with DAST (5.6 g, 35 mmol) at −78° C. The mixture was stirred at −78° C. for 3 h. The reaction was quenched by sat. aq. NaHCO₃, and then extracted with EA. The combined organic layer was dried over anhydrous, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give pure 40-7 (3.1 g, 18%) as a white solid.

Compound 40-7 (4.1 g, 5.7 mmol) in sat. NH₃/MeOH (100 mL) was stirred at R.T. for 16 h, and concentrated at low pressure. The residue was re-dissolved in anhydrous DCM (300 mL), and was treated with AgNO₃ (27.0 g, 160 mmol), collidine (22 mL) and MMTrCl (23.0 g, 75.9 mmol) in small portions under N₂. The mixture was stirred at R.T. for 16 h. The mixture was filtered, and the filtrate was washed with sat. NaHCO₃ solution and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give the pure intermediate. The intermediate was dissolved in a solution of TBAF/THF (1N, 20 mL). The mixture was stirred at R.T. for 2 h and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=50/1) to give pure 40-8 (3.0 g, 86%) as a white solid.

To a solution of 40-8 (3.0 g, 4.9 mmol) in THF (50 mL) was added imidazole (840 mg, 12 mmol), PPh₃ (3.2 g, 12 mmol), and I₂ (2.4 g, 9.2 mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reaction was quenched by sat. aq. Na₂S₂O₃, and then extracted with EA. The combined organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give crude 40-9 (4.2 g, >100%, containing TPPO) as a white solid.

To a solution of crude 40-9 in anhydrous THF (30 mL) was added DBU (2.7 g, 18 mmol), and heated to 80° C. The mixture was stirred for 1 h and checked by LCMS. The mixture was quenched by water, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give 40-10 (2.0 g, 69%) as a white solid.

To an ice-cooled solution of 40-10 (2.0 g, 3.38 mmol) in anhydrous MeCN (15 mL) was added NIS (777 mg, 3.5 mmol) and NEt₃.3HF (536 g, 3.3 mmol) at 0° C. The mixture was stirred at R.T. for 16 h and checked by LCMS. After completion, the mixture was quenched by sat. Na₂SO₃ and sat. NaHCO₃ solution, and extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA=10/1 to 3/1) to give 40-11 (2.1 g, 84.0%) as a white solid.

To a solution of crude 40-11 (2.1 g, 2.85 mmol) in anhydrous DCM (100 mL) was added DMAP (490 mg, 4 mmol), and BzCl (580 mg, 4 mmol) at 0° C. The mixture was stirred overnight and checked by LCMS. The reaction was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA=8/1 to 3/1) to give 40-12 (2.0 g, 83.4%) as a white solid.

To a solution of 40-12 (2.0 g, 2.4 mmol) in anhydrous DMF (60 mL) was added NaOBz (3.3 g, 23.0 mmol) and 15-crown-5 (5.11 g, 23 mmol). The mixture was stirred at 110° C. for 36 h. The reaction was quenched by water, and the mixture was extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=5/1 to 3/1) to give 40-13 (830 mg, 42.0%) as a white solid. ESI-MS: m/z 836.11 [M+H]⁺.

A solution of 40-13 (831 mg, 1.0 mmol) in anhydrous n-butylamine (4 mL) was stirred at R. T. for 3 h under N₂ atmosphere. The reaction was monitored by TLC. The solvent was evaporated in vacuo, and the residue was purified by silica gel column (MeOH in DCM from 0% to 10%) to give the crude product, which as re-purified using silica gel column to give 40-14 as a light pink solid (563 mg).

To a solution of 40-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL) was added imidazole (78.6 mg, 1.16 mmol) and TBSCl (202 mg, 1.34 mmol) at 0 to 5° C. The mixture was stirred at R. T. for 15 h. The reaction was quenched by adding absolute EtOH (0.3 mL). The solution was concentrated to dryness under reduced pressure, and co-evaporated with toluene 3 times. The residue was dissolved in EA (150 mL), and washed with water, sat. NaHCO₃, and brine. The combined organic layer was dried over Na₂SO₄, filtered and evaporated at low pressure. The residue was purified by silica gel column (0-20% EA in hexanes) to give 40-15 (303 mg) as a white solid.

To a solution of 40-15 (303 mg, 0.41 mmol), AgNO₃ (208 mg, 1.23 mmol) and collidine (0.55 mL, 4.51 mmol) in anhydrous DCM (4 mL) was added MMTrCl (378 mg, 1.3 mmol) under N₂. The mixture was stirred at R. T. overnight under N₂, and monitored by TLC. The mixture was filtered through pre-packed celite filter, and the filtrate was washed with water and, 50% aqueous citric acid, and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (EA in hexanes from 0% to 30%) to give 40-16 (374 mg, 90%).

To a solution of 40-16 (374 mg, 0.37 mmol) in anhydrous THF (4 mL) was added 1.0 M solution of TBAF (0.74 mL, 0.74 mmol) at 0 to 5° C. The mixture was stirred at R.T. for 1 h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to give the crude product, which was purified by silica gel column (EA in hexanes from 0% to 50%) to give 40-17 (265 mg).

To a stirred solution of 40-17 (187.5 mg, 0.16 mmol) in anhydrous CH₃CN (2.5 mL) was added N-methylimidazole (136 μL, 1.66 mmol) at 0-5° C. (ice/water bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (214 mg, 0.62 mmol, dissolved in 0.5 mL of CH₃CN). The solution was stirred at R.T. for 3 h, and then diluted with EA followed by the addition of water (15 mL). The solution was washed with H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give (single isomers) of 40-18 (108 mg) Elution of the latter fraction gave (single isomers) of 40-19 (120 mg) as glassy solid.

Compound 40-18 (108 mg, 0.089 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 40 (26.6 mg) as a white foam. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.89 (s, 1H), 7.33-7.29 (m, 2H), 7.20-7.13 (m, 3H), 7.17 (m, 1H), 6.62 (d, J=15.6 Hz, 1H), 5.39 (t, J=25.2 Hz, 1H), 4.75-4.42 (m, 6H), 3.92 (t, J=8.8 Hz, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H); ³¹P NMR (CD₃OD-d₄) δ 4.04 (s); ESI-LCMS: m/z=665.2 [M+H]⁺.

Compound 41 (44.4 mg, single isomer) was obtained according to the procedure described for compound 40 using 40-19. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H),), 7.32 (t, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 2H), 7.16 (t, J=7.6 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 4.68-4.60 (m, 2H), 4.54-4.39 (m, 3H), 3.93-3.89 (m, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.75-1.5 (m, 5H), 1.48-1.23 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.95 (s), −155.84-155.99 (m); ³¹P NMR (CD₃OD-d₄) δ3.94 (s); ESI-LCMS: m/z=665.15 [M+H]⁺.

Example 20 Compound 49

To a solution of triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.33 mmol, prepared from 110 mg of bis(POC)phosphate and 46 μL of Et₃N) in THF was added 49-1 (91 mg, 0.11 mmol). The mixture evaporated and rendered anhydrous by co-evaporating with pyridine follow by toluene. The residue was dissolved in anhydrous THF (1.5 mL) and cooled in an ice-bath. Diisopropylethyl amine (0.19 mL, 10 eq.) was added, followed by BOP-Cl (0.14 g, 5 eq.), and 3-nitro-1,2,4-triazole (63 mg, 5 eq.). The mixture was stirred 0° C. for 90 mins, diluted with EtOAc (30 mL), washed with sat. aq. NaHCO₃, brine, and dried (Na₂SO₄). The residue was purified on silica (10 g column) with CH₂Cl₂/i-PrOH solvent system (2-10% gradient) to obtain 49-2 (13 mg, 10%) and 49-3 (95 mg, 58%).

A solution of 49-2 and 49-3 (13 mg and 95 mg, respectively) in 80% aq. HCOOH (3 mL) was stirred at R.T. for 3 h, then evaporated and co-evaporated with toluene. The residue was purified on silica (10 g column) with CH₂Cl₂/MeOH (4-10% gradient) to obtain compound 49 in (42 mg, 94%) yield. MS: m/z=628 [M+1]⁺.

Example 21 Compound 52

Compound 52-2 (158 mg, 50%) was from 52-1 (0.21 g; 0.35 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.54 mmol) with DIPEA (0.18 mL), BopCl (178 mg), and 3-nitro-1,2,4-triazole (80 mg) in THF (4 mL).

A solution of 52-2 (158 mg) in acetonitrile (1 mL) and HCl (4 N/dioxane; 85 μL) was stirred at R.T. for 30 mins. The reaction was quenched with MeOH and concentrated. The residue was purified on silica gel (10 g column) with CH₂Cl₂/i-PrOH (3-10% gradient) to give compound 52 (85 mg, 76%). MS: m/z=656 [M+1]⁺.

Example 22 Compound 11

A mixture of 11-1 (170 mg, 0.19 mmol) and methanolic ammonia (7 N; 3 mL) was stirred at R.T. for 8 h, concentrated and purified on silica gel (10 g column) with CH₂Cl₂/MeOH (4-11% gradient) to give 11-2 (100 mg, 90%).

Compound 11-2 was rendered anhydrous by co-evaporating with pyridine, followed by toluene. To a solution of 11-2 (24 mg, 0.04 mmol), and N-methylimidazole (17 μL, 5 eq.) in acetonitrile (1 mL) was added the phosphorochloridate (50 mg, 3.5 eq.) in 2 portions in 6 h intervals. The mixture was stirred at R.T. for 1 d and evaporated. Purification on silica (10 g column) with CH₂Cl₂/MeOH (4-12% gradient) yielded 11-3 (10 mg, 28%).

A solution of 11-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred 3 h at R.T. The mixture was evaporated and purified on silica (10 g column) with CH₂Cl₂/MeOH (5-15% gradient) to give compound 11 (3 mg, 50%). MS: m/z=624 [M−1]⁻.

Example 23 Compound 14

A mixture of 14-1 (1.2 g, 4.3 mmol), PTSA monohydrate (0.82 g, 1 eq.), and trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) was stirred overnight at R.T. The reaction was neutralized with 7 N NH₃/MeOH and a white solid removed by filtration. The residue was dissolved in THF (10 mL) and treated with 80% aq. AcOH (5 mL). The mixture was kept at R.T. for 45 mins and then evaporated. The residue was purified on silica gel (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) to give 14-2 (1.18 g, 87%).

Compound 14-3 (137 mg, 75%) was prepared from 14-2 (93 mg, 0.29 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.44 mmol) with DIPEA (0.2 mL), BopCl (147 mg), and 3-nitro-1,2,4-triazole (66 mg) in THF (3 mL). Purification was done with CH₂Cl₂/i-PrOH solvent system (3-10% gradient).

A solution of 14-3 (137 mg) in 80% aq. HCOOH was stirred at R.T. for 2 h, and then concentrated. The residue was co-evaporated with toluene and then MeOH containing a small amount of a small amount of Et₃N (2 drops). Purification on silica (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) gave compound 14 (100 mg, 77%). MS: m/z=1175 [2M−1]⁻.

Example 24 Compound 16

Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 mins. The mixture was heated to 70° C., and stirred overnight. The solution was cooled to R.T. and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 16-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 16-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) and collidine (40 mL) in anhydrous DCM (200 mL) was added MmTrCl (46.0 g, 149.2 mmol) in small portions under N₂. The mixture was stirred at R.T. for 3 h under N₂. The reaction was monitored by TLC. The mixture was filtered, and the filter was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crude 16-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C., and slowly warmed to R.T. Compound 16-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred overnight at R.T. The reaction was monitored by TLC, and the mixture was concentrated at low pressure. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 16-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 16-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrous pyridine 3 times. To an ice-cooled solution of 16-4 in anhydrous pyridine (100 mL) was added TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. The reaction was checked by LCMS (about 70% was the desired product). The reaction was quenched with H₂O, and the solution was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crude 16-5 (25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 16-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was added NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and refluxed overnight. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), washed with brine, and dried over anhydrous Na₂SO₄. The organic solution was evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give the crude product. To a solution of the crude product in dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and heated to 60° C. The mixture was stirred overnight, and checked by LCMS. The reaction was quenched with sat. NaHCO₃, and the solution was extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 16-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 16-6 (8.0 g, 13.8 mmol) in dry MeCN (100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at 0° C. The mixture was stirred at R.T. for 18 h and checked by LCMS. After the reaction was complete, the reaction was quenched with sat Na₂SO₃ and sat. NaHCO₃ solution. The solution was extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 50%) to give 16-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of crude 16-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was added DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. The mixture was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 16-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 16-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 16-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene 3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS, and the mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 16-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridate reagent (338.1 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS. The mixture was diluted with 10% NaHCO₃ solution, and extracted with EA. The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-11 (240 mg, 53.3%) as a solid. ESI-MS: m/z 925 [M+H]⁺.

Compound 16-11 (240.0 mg, 0.26 mmol) was treated with 80% AcOH (10 mL), and the mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS. The mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 3%) to give compound 16 (87.6 mg, 51.7%) as a solid. ESI-MS: m/z 653 [M+H]⁺.

Example 25 Compound 30

To a stirred solution of compound 25 (60 mg, 0.22 mmol) in anhydrous THF (2.0 mL) was added N-methylimidazole (0.142 mL, 1.73 mmol) at 0° C. (dry ice/acetone bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (235 mg, 0.68 mmol, dissolved in THF (2 mL). The resulting solution was stirred at 0° C. for 1 h, and the temperature was raised up-to 10° C. over the next 1 h. The reaction left at 10° C. for 3 h. The mixture was cooled to 0 to 5° C., diluted with EA, and water (5 mL) was added. The solution was washed with H₂O and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CH₃CN/H₂O. The compound was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization gave a white foam. The produce was re-dissolved in EtOAc, washed with 50% aqueous citric acid solution, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum, and lyophilized to give two isomers (Rp/Sp) of compound 30 (6.3 mg). MS: m/z 586.05 [M−H]⁻.

Example 26 Compound 17

Compound 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 mins until a clear solution was observed. The mixture was heated to 70° C., and stirred overnight. The solution was cooled to R.T., and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 17-2 (48.0 g, 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 17-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) and collidine (40 mL) in anhydrous DCM (200 mL) was added MmTrCl (46.0 g, 149.2 mmol) in small portions under N₂. The mixture was stirred at R.T. for 3 h under N₂. Completion of the reaction was determined by TLC. After filtration, the filtrate was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crude 17-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C., and slowly warmed to R.T. Compound 17-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred overnight at R.T. Completion of the reaction was determined by TLC and LCMS. The mixture was concentrated at a low pressure, diluted with H₂O (100 mL), and extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 17-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrous pyridine 3 times. To an ice-cooled solution of 17-4 (32.0 g, 53.5 mmol) in anhydrous pyridine (100 mL) was added a solution of TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. The reaction was monitored by LCMS, and quenched with H₂O. The solution was concentrated at low pressure, and the residue was dissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at a low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crude 17-5 (25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 17-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was added NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and the mixture was refluxed overnight. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was dissolved in EA (100 mL). The solution was washed with brine, and dried over anhydrous Na₂SO₄. The organic solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give a crude product. To a solution of the crude product in dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to 60° C. and stirred overnight. The reaction was monitored by LCMS. The reaction was quenched with sat. NaHCO₃ solution, and the solution was extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 17-6 (8.0 g, 13.8 mmol) in anhydrous MeCN (100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at 0° C. The mixture was stirred at R.T. for 18 h, and the reaction was checked by LCMS. After the reaction was completed, the reaction was quenched with sat. Na₂SO₃ solution and sat. NaHCO₃ solution. The solution was extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 50%) to give 17-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of 17-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was added DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. The mixture was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 17-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 17-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 17-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 17-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene 3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h. at R.T. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give product 17-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 17-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridate reagent (326.3 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture was stirred for 18 h at R.T. and monitored by LCMS. The mixture was diluted with 10% NaHCO₃ solution, and extracted with EA (3×30 mL). The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 17-11 (210 mg, 47.5%) as a solid. ESI-MS: m/z 913.0 [M+H]⁺.

Compound 17-11 (210 mg, 0.26 mmol) was treated with 80% of AcOH (15 mL), and the mixture was stirred for 18 h at R.T. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 3%) to give compound 17 (71.8 mg, 48.7%) as a solid. ESI-MS: m/z 641.3 [M+H]⁺.

Example 27 Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76

Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76 were prepared in a manner similar to method for preparing compound 6. After the addition of POCl₃, the mixture was kept at R.T. for 20-40 mins. The reaction was controlled by LCMS and monitored by the appearance of corresponding nucleoside 5′-monophosphate. After completion of the reaction, tetrabutylammonium salt of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h at ambient temperature, the reaction was diluted with water (10 mL). The triphosphate (eluted at 75-80% B) were obtained as described for compound 6.

MS ³¹P NMR Structure [M − 1]⁻ P(α) P(β) P(γ)

556.2 −10.92   −11.03(d) −23.18(t) −11.86   −11.98(d)

516.1  −7.49    −7.61(d) −22.42(t) −12.17   −12.30(d)

554.0 −10.94   −11.06(d) −23.25(t) −11.85   −11.97(d)

525.2 −8.53(bs) −22.61 (bs) −12.17   −12.29(d)

564.4 −11.05 (bs) −23.25 (bs) −11.96   −12.08(d)

566.0 −10.92   −11.04(d) −23.18(t) −11.93  −1(d)

533.3 −10.89   −11.01(d) −23.31(t) −12.49  −1(d)

513.8 −8.66(bs) −22.80(t) −12.17   −12.29(d)

517.7 −13.73   −13.60(d) −25.98(t) −15.18   −15.06(d)

539.5 −7.42 (br.s) −22.57(t) −12.23   −12.34(d)

513.1  −6.36    −6.49(d) −22.49(t) −12.20   −12.33(d)

526.8 −10.96   −11.08(d) −23.33(t) −12.41   −12.53(d)

533.4 −10.78 (br.s) −23.22(t) −12.24   −12.36(d)

The following compounds can also be prepared using a method similar to the method described in Example 27:

Example 28 Compound 10

Compound 10-1 (5 g, 8.79 mmol) was co-evaporated with anhydrous pyridine. To an ice-cooled solution of 10-1 in anhydrous pyridine (15 mL) was added TsCl (3.43 g, 17.58 mmol), and stirred for 1 h at 0° C. The reaction was checked by LCMS and TLC. The reaction was quenched with H₂O, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄, and evaporated at low pressure. Compound 10-2 (6.35 g, 100%) was used for next step directly.

To a solution of 10-2 (31.77 g, 43.94 mmol) in acetone (300 mL) was added NaI (65.86 g, 439.4 mmol), and heated to reflux overnight. The reaction was checked by LCMS. The reaction was quenched with sat. Na₂S₂O₃ solution, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 6%) to give 10-3 (11.5 g, 38%) as a white solid.

To a solution of 10-3 (11.5 g, 16.94 mmol) in dry THF (120 mL) was added DBU (12.87 g, 84.68 mmol), and heated to 60° C. The reaction was stirred overnight and checked by LCMS. The reaction was quenched with sat. NaHCO₃ solution, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 10-4 (5.5 g, 54%) as a white solid.

To an ice-cooled solution of 10-4 (500 mg, 0.90 mmol) in dry DCM (20 ml) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97 mmol) in dry DCM (20 mL). The reaction was stirred for 3 h., and checked by LCMS. The reaction was quenched with sat Na₂S₂O₃ solution and sat. NaHCO₃ solution, and the mixture was extracted with DCM. The organic layer was dried by anhydrous Na₂SO₄, and evaporated at low pressure to give crude 10-5 (420 mg, 66%).

To a solution of crude 10-5 (250 mg, 0.36 mmol) in dry DCM (8 mL) was added DMAP (0.28 g, 2.33 mmol), TEA (145 mg, 1.44 mmol) and BzCl (230 mg, 1.62 mmol) in a solution of DCM (2 mL). The reaction was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution and brine. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give crude 10-6 (150 mg, 46%).

To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60° C. The mixture was diluted with H₂O, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]⁺.

A mixture of 10-7 (25 mg) and BuNH₂ (0.8 mL) was stirred overnight at R.T. The mixture was evaporated and purified on silica gel (10 g column) with CH₂Cl₂/MeOH (4-15% gradient) to yield 10-8 (15 mg, 91%).

A mixture of 10-8 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4 N HCL/dioxane (19 uL) was stirred at R.T. for 45 mins. The mixture was diluted with MeOH and evaporated. The crude residue was treated with MeCN, and the solid was filtered to yield compound 10 (7 mg). MS: m/z=314 [M−1]⁻.

Example 29 Compounds 36 and 37

To a solution of 36-1 (150 mg, 0.24 mmol) in DCM (2.0 mL), triethylamine (141 μL, 2.0 mmol) was added at R.T. The mixture was cooled to 0 to 5° C. (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (45 μL, 0.26 mmol, prepared according to a procedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added. The mixture was stirred at 0 to 5° C. (ice/water bath) for 15 mins, followed by N-methylimidazole (40 μL, 0.49 mmol). The mixture was stirred for 1 h at 0 to 5° C. TLC showed the absence of starting material 36-1. EA (100 mL) was added, followed by water. The organic layer was washed with H₂O, sat. aq. NH₄Cl solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 10% iPrOH/DCM to give 36-2a (16.9 mg, faster eluting isomer) and 36-2b (72.7 mg, slower eluting isomer).

Compounds 36-2a and 36-2b were deprotected using a procedure described herein. Compound 36 (7.3 mg, single isomers from 36-2a (16.5 mg, 0.0235 mmol)) and compound 37 (29.0 mg. single isomers from 36-2b (72.7 mg, 0.1 mmol)) were obtained.

Compound 36: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.94 (s, 1H), 6.32 (s, 1H), 6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, 1H), 4.65-4.50 (m, 3H), 1.45-1.39 (s, 9H), 1.2 (s, 3H), ¹⁹F NMR (CD₃OD-d₄) δ −120.3 (s); ³¹P NMR (CD₃OD-d₄) δ −5.19 (s); ESI-LCMS: m/z=448.05 [M+H]⁺. Compound 37: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.98 (s, 1H), 6.34 (s, 1H), 5.78-5.64 (br s, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1 (s, 3H), ¹⁹F NMR (CD₃OD-d₄) δ −121.3 (s); ³¹P NMR (CD₃OD-d₄) δ −7.38 (s); ESI-LCMS: m/z=448.05 [M+H]⁺.

Example 30 Compound 48

To a solution of 48-1 (600 mg, 1.29 mmol) in anhydrous CH₃CN (4 mL) was added DMAP (315 mg, 2.59 mmol), TEA (391 mg, 3.87 mmol) and TPSCl (782 mg, 2.58 mmol). The mixture was stirred for 3 h. under N₂. A solution of NH₃ in THF (2 mL) was added, and stirred for 1 h. The reaction was quenched with sat. NH₄Cl solution, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified by column chromatography to provide 48-2 (370 mg, 62%) as a white foam solid.

Compound 48-2 (370 mg, 1.48 mmol) in methanolic ammonium was stirred at R.T. for 4 h. The solution was concentrated to dryness to give compound 48 (200 mg, 91%) as a white solid. ESI-MS: m/z 275.9 [M+H]⁺.

Example 31 Compounds 18 and 19

The diastereomers of compound 2 were separated by RP-HPLC. A gradient of 10-43% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4 u particle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 19 (29.5 mins) and compound 18 (30.1 mins). Pure fractions were lyophilized to produce a white powder. Compound 19: ³¹P-NMR (DMSO-d6) 3.448 ppm; MS: m/z: 544 [M−1]⁻; Compound 18: ³¹P-NMR (DMSO-d6) 3.538 ppm; MS: m/z: 544 [M−1]⁻.

Example 32 Compounds 20 and 21

The diastereomers of compound 3 were separated by RP-HPLC. A gradient of 25-52% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4 u particle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 21 (24.8 mins) and compound 20 (25.3 mins). Pure fractions were lyophilized to produce a white powder. Compound 21: ³¹P-NMR (DMSO-d6) 3.492 ppm; MS: m/z: 584 [M−1]⁻. Compound 20: ³¹P-NMR (DMSO-d6) 3.528 ppm; MS: m/z: 584 [M−1]⁻.

Example 33 Compound 13

Compound 2-1 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and 2M solution of isopropylmagnesium bromide in THF (0.1 mL) was added at 0° C. The reaction was left for 1 h at R.T., and phenyl(isopropyl-L-alaninyl) thiophosphorochloridate was added (0.3 mmol). The mixture was left overnight at R.T. LSMS analysis showed about 20% of unreacted starting material. The same amount of Grignard reagent and thiophosphorochloridate were added, and the mixture was heated at 37° C. for 4 h. The reaction was quenched with NH₄Cl. The product was extracted with EA, washed with brine, dried over Na₂SO₄, and evaporated. The resulting oil was dissolved in 80% formic acid (4 mL) and in 1 h evaporated. Compound 13 was purified by RP HPLC in gradient of methanol in water from 30% to 95% on Synergy 4 u Hydro-RP column (Phenominex) yielding a colorless solid. Compound 13 (7 mg, yield 12.5%). MS: m/z: 560.0 [M−1]⁻.

Example 34 Compound 39, Bis-lithium Salt

Compound 39-1 was synthesized using a procedure similar for preparing compound 2 using alanine benzyl ester hydrochloride. LCMS: m/z 592 [M−1]⁻.

To a solution of 39-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3 mL) was added aqueous triethylammonium acetate (2M, 2 mL, 4 mmol) followed by Pd—C (10%, 100 mg). The mixture was hydrogenated (balloon) for 2 h, and monitored by HPLC. The catalyst was filtered off, and the filtrate was concentrated to dryness. The residue was suspended in 3% solution of lithium perchlorate in acetone (25 mL). The solid was isolated by filtration, rinsed with acetone and dried under vacuum to give compound 39 (bis-lithium salt) (731 mg, 90%). LCMS: m/z 426 [M−1]⁻.

Example 35 Compound 55

Compound 1 (40 mg, 0.14 mmol) and triethylammonium bis(pivaloyloxymethyl)phosphate (0.21 mmol, prepared from 80 mg of bis(pivaloyloxymethyl)phosphate and 30 μL of Et₃N) were rendered anhydrous by coevaporating with pyridine, followed by toluene. The evaporated residue was dissolved in anhydrous THF (2 mL) and cooled in an ice-bath. Diisopropylethyl amine (73 μL, 3 eq.), BopCl (71 mg, 2 eq.), and 3-nitro-1,2,4-triazole (32 mg, 2 eq.) were added. The mixture was stirred at 0° C. for 90 mins. The mixture was then diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). Purification on silica gel column with CH₂Cl₂/i-PrOH solvent system (4-10% gradient) followed by RP-HPLC purification (A: water, B: MeCN) yielded compound 55 (13 mg, 16%). MS: m/z=1167 [2M−1].

Example 36 Compound 45

Compound 45-1 (15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL) at R.T. The mixture was stirred at 110° C. for 12 h, and then concentrated at a low pressure. The residue was dissolved in DCM, and the solution was washed with brine. The organic phase was dried over anhydrous Na₂SO₄, and then concentrated at a low pressure. The residue was purified by column chromatography (5% MeOH in DCM) to give 45-2 (11.0 g, 88.9%) as a white solid.

Compound 45-2 (12.0 g, 24.79 mmol) was treated with NH₃ in MeOH (200 mL, 7 M) at R.T. The solution was stirred at R.T. for 12 h, and then concentrated at a low pressure. The residue was purified by column chromatography (10% MeOH in DCM) to give 45-3 (6.5 g, 95.0%) as a white solid.

To a stirred suspension of 45-3 (4.3 g, 15.58 mmol), PPh₃ (8.16 g, 31.15 mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in anhydrous THF (45 mL) was added a solution of I₂ (7.91 g, 31.15 mmol) in THF (100 mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirred overnight. The mixture was quenched with MeOH (100 mL). The solvent was removed at a low pressure, and the residue was re-dissolved in a mixture of EA and THF (0.2 L, 10:1). The organic phase was washed with sat. Na₂S₂O₃ aq. (2×). The aqueous phase was extracted with a mixture of EA and THF (0.2 L, 10:1, 2×). The concentrated organic phase was dried over anhydrous Na₂SO₄. The residue was purified on a silica gel column (0-10% MeOH in DCM) to afford 45-4 (5.1 g, 85.0%) as a white solid.

Compound 45-4 (800 mg, 2.07 mmol) was dissolved in a mixture of DBU (4 mL) and THF (4 mL) at R.T. under N₂. The solution was stirred at R.T. for 1 h. The mixture was neutralized with HOAc, and extracted with a mixture of EA and THF (10:1, 40 mL). The organic phase was washed with brine, and dried over anhydrous Na₂SO₄. The concentrated organic phase was purified by column chromatography (0-10% MeOH in DCM) to give 45-5 (240 mg, 44.9%) as a white solid.

To an ice-cooled solution of 45-5 (1.20 g, 4.65 mmol) in anhydrous MeCN (12 mL) was added NIS (1.57 g, 6.97 mmol) and TEA.3HF (1.12 g, 6.97 mmol) under N₂. The mixture was stirred at R.T. for 5 h. The reaction was quenched with sat. NaHCO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH in DCM) to give 45-6 (0.91 g, 48.6%) as a white solid.

To a stirred solution of 45-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12 mL) was added BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol) and DMAP (0.72 g, 5.94 mmol) successively at R.T. The mixture was stirred at R.T. for 12 h. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure. The residue was purified by column chromatography (0-5% MeOH in DCM) to give 45-7 (1.2 g, 66.2%) as a white solid.

Tetra-butyl ammonium hydroxide (25.78 mL, 51.78 mmol) was neutralized with TFA (4.3 mL) to pH=4, and the solution was added to a solution of 45-7 (1.09 g, 2.14 mmol) in DCM (30 mL). m-CPBA (1.85 g, 10.74 mmol) was added portion-wise under vigorous stirring, and the mixture was stirred for 12 h. The mixture was diluted with EA (100 mL), and washed with sat. sodium bicarbonate. The organic phase was concentrated at low pressure. The residue was purified by column chromatography (50% EA in PE) to give 45-8 (350 mg, 41.1%) as a white solid.

Compound 45-8 (280 mg, 0.704 mmol) was treated with NH₃ in MeOH (10 mL, 7 M) at R.T. The mixture was stirred at R.T. for 2 h. The mixture was concentrated at a low pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give compound 45 (110 mg, 53.1%) as a white solid. ESI-LCMS: m/z 295.1 [M+H]⁺.

Example 37 Compound 54

To an ice-cooled solution of 54-1 (10 g, 42 mmol) in anhydrous MeCN (200 mL) was added TEA.3HF (10 g, 62.5 mmol) and NIS (28 g, 126 mmol). The mixture was stirred at R.T. for 1.5 h, and monitored by LCMS. After the reaction was completed, the mixture was concentrated at a low pressure. The residue was purified by silica gel column chromatography (15% MeCN in DCM) to give 54-2 (12 g, 74%) as a yellow solid.

To a solution of 54-2 (22 g, 57 mmol) in anhydrous DCM (200 mL) was added DMAP (21 g, 171 mmol) and BzCl (17.6 g, 125 mol). The mixture was stirred for 5 h at R.T., and monitored by LCMS. The solution was washed with sat. NaHCO₃ solution, brine and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-3 (30 g, 88%) as a white foam.

To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mL), and the solution was washed with sat. NaHCO₃ solution, and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-4 (3 g crude, 46.1%) as an oil.

Compound 54-4 (3 g, crude) was treated with NH₃ in MeOH (120 mL, 7 M). The mixture was stirred for 3 h and monitored by TLC. The solution was concentrated at low pressure. The residue was purified by silica gel column chromatography (10% isopropanol in DCM) to give 54-5 (1.0 g, 67%) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=1.19 (s, 3H), 3.76-3.82 (m, 2H), 4.02 (d, J=19.8 Hz, 1H), 5.70 (d, J=8.07 Hz, 1H), 6.27 (s, 1H), 7.89 (d, J=8.07 Hz, 1H).

Compound 54-5 (100 mg, 0.36 mmol) was co-evaporated with toluene 3 times. To a stirred solution of 54-5 (100 mg, 0.36 mmol) in a mixture of MeCN (1.0 mL) and NMI (295 mg, 3.6 mmol) was added a solution of 54-C (255.6 mg, 0.72 mmol, preparation described below) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and diluted with EA (20 mL). The organic layer was washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure. The residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product. The product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 54 (46.7 mg, 23.3%) as a white solid. ESI-LCMS: m/z 618 [M+Na]⁺.

To a stirred solution of 54-A (2.0 g, 13.16 mmol) and naphthalen-1-ol (1.89 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. After addition, the mixture was gradually warmed to R.T., and stirred for 2 h. The solution was cooled to −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed by TEA (2.66 g, 26.29 mmol) in DCM (20 mL) dropwise. The mixture was gradually warmed to R.T., and stirred for 2 h. The organic solvent was removed at low pressure. The residue was dissolved in methyl-butyl ether. The precipitate was filtered, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 54-C (1.0 g, 24.8%) as a colorless oil.

Example 38 Compounds 56 and 57

To a solution of 54-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) in anhydrous MeCN (4 mL) was added a solution of 57-C (736 mg, 2.17 mmol, preparation described below) in anhydrous MeCN (1 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and diluted with EA (30 mL). The organic layer was washed with water and brine. The organic phase was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column (iPrOH in DCM from 1% to 5%) to give crude compound 56 (276 mg, crude). Crude compound 56 (96 mg) was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 56 (46 mg, 47.9%) as a white solid. ESI-LCMS: m/z 560 [M−F]⁺.

To a solution of compound 56 (180 mg, 0.31 mmol) in anhydrous pyridine (6 mL) was added acetic anhydride (158 mg, 1.54 mmol) dropwise at 0° C. The mixture was stirred at R.T. overnight. The solution was quenched with water and concentrated at a low pressure. The residue was dissolved in EA (10 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure. The residue was purified by silica gel column (i-PrOH in DCM from 1% to 3%) to give crude compound 57 (172 mg). Crude compound 57 was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 57 (46 mg, 23.8%) as a white solid. ESI-LCMS: m/z 602.3 [M−F]⁺.

Compound 56-C (1.02 g, 23%, a colorless oil) was prepared using a procedure similar to the preparation of 54-C using 54-A (2.00 g, 13.16 mmol) and 4-chlorophenol (1.68 g, 13.16 mmol).

Example 39 Compound 61

Compound 25 (109 mg, 0.39 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.6 mmol, prepared from 195 mg of bis(isopropyloxycarbonyloxymethyl)phosphate and 85 μL of Et₃N) were rendered anhydrous by coevaporating with pyridine, followed by toluene. The residue was dissolved in anhydrous THF (3 mL) and cooled in an ice-bath. Diisopropylethyl amine (0.2 mL, 3 eq.), BopCl (190 mg, 2 eq.), and 3-nitro-1,2,4-triazole (81 mg, 2 eq.) were added, and the mixture was stirred at 0° C. for 90 mins. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). Purification on silica gel column with CH₂Cl₂/i-PrOH (4-10% gradient) followed by RP-HPLC purification (A: 0.1% HCOOH in water, B: 0.1% HCOOH in MeCN) yielded compound 61 (28 mg, 12%). ¹H-NMR (CDCl₃): δ 7.24 (d, 1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 4.38 (m, 2H), 4.1 (b, 1H), 2.88 (d, 1H), 1.47 (d, 3H), 1.33 (m, 12H).

Example 40 Compound 74

Dry nucleoside (0.05 mmol) was dissolved in a mixture of PO(OMe)₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15 mins. at 42° C., then cooled to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃ (0.009 mL, 0.11 mmol). The mixture was kept at R.T. for 20-40 mins and monitored for the formation of compound 74 by LCMS. The reaction was quenched with water and isolated by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. MS: m/z 396.5 [M−1]⁻.

Example 41 Compound 68

The nucleoside (140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5 mL). The mixture was kept for 2 h at R.T., and the amine was then evaporated. The residue was dissolved in EtOAc, and the organic layer was washed twice with 10% citric acid, dried over Na₂SO₄, and evaporated. The residue purified by column chromatography on silica gel in linear gradient of methanol in DCM from 0% to 12% over 10 column volumes. The fractions containing the product were concentrated and treated with 80% HCOOH for 1 h at R.T. The mixture was evaporated to dryness, and suspended in CH₃CN. The precipitate was separated, washed with CH₃CN (1 mL) and dried to yield compound 68 (27 mg, 50%). MS: m/z 326.5 [M−1]⁻.

Example 42 Compound 62

Compound 45 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept for 5 d at R.T. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The phosphoroamidate was isolated by silica gel chromatography in a gradient of methanol in DCM from 3% to 10%. The corresponding fractions were concentrated and re-purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol in DCM from 3% to 95% containing 0.1% formic acid was used for elution. Compound 62 was obtained as a mixture Rp and Rs isomers (9 mg, 16%). MS: m/z 562.1[M−1]⁻.

Example 43 Compound 72

Compound 47 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept overnight at 40° C. The temperature was increased to 65° C. and heated for 1 h. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The azido-phosphoramidate was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 30% to 100% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The azido-phosphoramidate (8 mg) was dissolved in pyridine/Et₃N (3 mL, 8:1 v/v) and cooled to 0° C. H₂S gas was bubbled through the solution for 10 min, and the reaction was kept for 1 h at R.T. The solvents were evaporated, and the residue isolated by RP HPLC. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer, to provide compound 72 (1.2 mg) as mixture Rp and Rs isomers. MS: m/z 544.1 [M+1]⁺.

Example 44 Compound 65

To a solution of 65-1 (23.0 g, 39.5 mmol) in anhydrous toluene (200 mL) was added DAST (31.9 g, 198 mmol) dropwise at −78° C., and the solution was stirred at −78° C. for 3 h. The mixture was quenched with sat. NaHCO₃, extracted with EA (2×200 mL) and dried over with anhydrous Na₂SO₄. The solution was concentrated to dryness under low pressure. The residue was purified on a silica gel column (50% EA in PE) to give 65-2 (16.5 g, 71%) as a yellow foam.

A mixture of 65-2 (16.0 g, 27.4 mmol) and NH₄F (3.0 g, 82.2 mmol) in methanol (100 mL) was stirred at 70° C. for 12 h. The reaction was cooled, and the salt was removed by filtration. The filtrate was concentrated to dryness at low pressure. The residue was purified on a silica gel column (3% MeOH in DCM) to give 65-3 (5.1 g, 69.0%) as a white foam.

To a stirred suspension of 65-3 (4.1 g, 15.2 mmol), PPh₃ (8.0 g, 30.4 mmol), imidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrous THF (40 mL) was added dropwise a solution of I₂ (5.8 g, 22.8 mmol) in THF (20 mL) at 0° C. The mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (100 mL), and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (4% MeOH in DCM) to give pure 65-4 (4.4 g, 77%) as a white solid. ESI-MS: m/z 381.1 [M+1]⁺.

To a stirred solution of 65-4 (2.5 g, 0.7 mmol) in anhydrous THF (3 mL) was added DBU (2.1 g, 14 mmol) at R.T., and the mixture was stirred at R.T. for 1 h. The reaction was quenched with HOAc, and diluted with 2-Me-tetrahydrofuran. The solution was washed with brine, dried over with anhydrous Na₂SO₄ and concentrated to dryness at low pressure. The residue was purified on a silica gel column (MeOH 5% in DCM) to give 65-5 (1.1 g, 68.9%) as a white foam.

To a stirred solution of 65-5 (800 mg, 3.17 mmol) in anhydrous CH₃CN (10 mL) was added TEA.3HF (510 mg, 3.17 mmol) and NIS (785 mg, 3.49 mmol) at 0° C. The mixture was stirred for 30 mins, gradually warmed to R.T., and stirred for 1 h. The mixture was quenched with sat. NaHCO₃ solution and Na₂S₂O₃ solution, and extracted with EA (2×20 mL). The organic layer was dried over with anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified on a silica gel column to give pure 65-6 (695 mg, 57.9%) as a yellow solid.

To a stirred solution of 65-6 (650 mg, 1.63 mmol) in pyridine (3 mL) was added BzCl (507 mg, 3.59 mmol) at 0° C., and stirred at R.T. for 12 h. The mixture was quenched with water, and concentrated to dryness under reducing pressure. The residue was purified on a silica gel column (EA 50% in PE) to yield 65-7 (550 mg, 67%) as a white foam.

Tetra-butylammonium hydroxide (9 mL as 54-56% aqueous solution, 72 mmol) was neutralized with TFA to pH˜4 (1.5 mL), and the mixture was added to a solution of 65-7 (375 mg, 0.75 mmol) in DCM (9 mL). m-Chloroperbenzoic acid (924 mg, 60-70%, 3.75 mmol) was added in portions with vigorous stirring, and the mixture was stirred overnight. The mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA 50% in PE) to give 65-8 (230 mg, 78.8%) as a white foam. ESI-MS: m/z 393.1 [M+1]⁺.

Compound 65-8 (120 mg, 0.24 mmol) was treated with 7N NH₃.MeOH (20 mL), and stirred for 5 h. The mixture was concentrated to dryness at low pressure. The residue was purified on a silica gel column (propan-2-ol 15% in DCM) to yield compound 65 (53 mg, 60.2%) as a white solid. ESI-MS: m/z 288.8 [M+1]⁺.

Example 45 Compound 70

To a solution of 70-1 (3.0 g, 18.0 mmol) and POCl₃ (1.35 g, 9.0 mmol) in DCM (80 mL) was added TEA (3.6 g, 36.0 mmol) in DCM (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. A solution of pentafluorophenol (1.65 g, 9.0 mmol) and TEA (0.9 g, 9.0 mmol) in DCM (20 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 15 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed by TBME and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (20% EA in PE) to give 70-2 (2.7 g, 62.7%) as a white solid. ESI-MS: m/z 491.1 [M+1]⁺.

To a stirred solution of 1-((3aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl)-2-methoxy-3a-methyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.47 mmol) in anhydrous THF (2 mL) was added a solution of t-BuMgCl (0.46 mL, 1M in THF) dropwise at 0° C. The mixture was stirred at R.T. for 40 mins, and re-cooled to 0° C. A solution of 70-2 (462 mg, 0.94 mmol) was added, and the mixture was stirred at R.T. for 4 h. The mixture was quenched with H₂O, and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated under reducing pressure. The residue was purified on a silica gel column (50% EA in PE) to give 70-3 as a white foam (230 mg, 78%).

Compound 70-3 (230 mg, 0.37 mmol) was dissolved in 80% HCOOH aqueous solution (20 mL), and the mixture was stirred at R.T. for 24 h. The solvent was removed at low pressure. The residue was purified on a silica gel column to give the crude product, which was purified by RP HPLC (HCOOH system) to give compound 70 as a mixture of two P-isomers (75 mg, 33%). ESI-TOF-MS: m/z 583.0 [M+H]⁺.

Example 46 Compound 75

To a solution of 75-1 (120 g, 0.26 mol) in CH₃CN (2.0 L) was added IBX (109 g, 0.39 mol), and refluxed for 12 h. The reaction was monitored by TLC and LCMS. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated at low pressure. The crude product was used directly for the next step.

Compound 75-2 (130 g, 0.26 mol) was co-evaporated with anhydrous toluene three times to remove H₂O. To a solution of 75-2 in THF (300 mL) was added dropwise vinyl magnesium bromide (700 mL, 0.78 mol, 1N in THF) over 30 min at −78° C. The mixture was stirred for about 1 h at R.T. After the starting material was consumed, the mixture was poured into a sat. NH₄Cl solution. The organic layer was washed with brine, dried with anhydrous Na₂SO₄ and filtered. The solution was concentrated at low pressure to get the crude product. To a solution of this crude product (170 g, 0.346 mol) in anhydrous CH₂Cl₂ was added TEA (105 g, 1.04 mol) and DMAP (84 g, 0.69 mol). Benzoyl chloride (146 g, 1.04 mol) was added slowly at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ and then washed with sat. aq. NaHCO₃. The combined aq. phase was extracted with DCM (100 mL), and the combined organic phase was dried with Na₂SO₄. After filtration, the solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give 75-3 (107 g, 52%).

Uracil (44.8 g, 0.4 mol) (co-evaporated with toluene twice) and NOBSA (81.4 g, 0.4 mol) were dissolved in CH₃CN (500 mL). The mixture was refluxed for 1.5 h and then slowly cooled to R.T. The mixture was treated with 75-3 (59 g, 0.1 mol) and TMSOTf (155 g, 0.7 mol), and then warmed to 60-70° C. for 12 h. The mixture was neutralized with a sat. NaHCO₃ solution, and extracted with EA (3×1000 mL). The solution was dried over anhydrous MgSO4, and evaporated at low pressure. The residue was purified using a silica gel column to give pure 75-4 (40 g, 69%) as a white solid.

To a solution of 75-4 (50 g, 0.086 mol) in DMF was added PMBCl (16 g, 0.1 mol) and K₂CO₃ (17.8 g, 0.13 mol) at 0° C., and the mixture was stirred at R.T. for 12 h. The mixture was quenched with water (100 mL), and extracted with EA (3×200 mL). The organic phase was concentrated at low pressure to give crude 75-5 (65 g) which was used in the next step without further purification.

To a solution of crude 75-5 (65 g, 0.086 mol) in MeOH/DCM (4/1) (200 mL) was added NaOMe (16.8 g, 0.3 mol), and the mixture was stirred at R.T. for 2.5 h. The reaction was quenched with dry ice, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and washed with brine. The organic layer was concentrated at low pressure, and the residue was purified using a silica gel column using 1% MeOH in CH₂Cl₂ to give 75-6 as a yellow foam (25 g, 75%).

To a solution of 75-6 (25.5 g, 0.065 mol) in DMF was added NaH (10.5 g, 0.26 mol) slowly at 0° C., and the mixture was stirred for 30 mins. BnBr (36.3 g, 0.21 mol) was added, and the mixture was stirred at R.T. for 12 h. The reaction was quenched with sat. NH₄Cl (aq.), and then extracted with EA (3×100 mL). The solution was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by a silica gel column using 10% EA in PE to give 75-7 (20 g, 46%) as a white solid.

To a solution of 75-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) in THF:H₂O (5:1) (100 mL) was added OsO₄ (2.6 g, 0.01 mol) at R.T., and the mixture was stirred at R.T. for 24 h. The mixture was quenched with a sat. Na₂S₂O₃ solution, and extracted with EA (3×100 mL). The organic layer was washed with brine, and dried over anhydrous MgSO₄. The solution was evaporated at low pressure to give the crude compound, which was used in the next step without further purification.

To a solution of the crude diol (0.03 mol) in MeOH:H₂O:THF (170 mL:30 mL:50 mL) was added NaIO₄ (9.6 g, 0.045 mol), and the mixture was stirred at R.T. for 2 h. After filtration, the filtrate was used directly in the next step. This solution was treated with NaBH₄ (1.8 g, 0.048 mol) at 0° C., and the mixture was stirred at R.T. for 30 mins. The mixture was quenched with MeOH, and evaporated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The solution was evaporated at low pressure, and the residue was purified by a silica gel column using 20% EA in EA to give 75-8 (12 g, 61% over three steps).

To a solution of 75-8 (14 g, 21 mmol) and DMAP (5.1 g, 42 mmol) in DCM (100 mL) was added MsCl (3.1 g, 27 mmol) at 0° C., and the mixture was stirred at R.T. for 40 mins. The reaction was quenched with sat. NaHCO₃ (aq.), and washed with HCl (0.2 N) solution. The organic phase was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by a silica gel column using 5% EA in PE to give mysolate product (14 g, 90%). The MsO-product (41 g, 55 mmol) was treated with TBAF (1 N in THF, 500 mL), and the mixture was stirred at 70-80° C. for 3 d. The mixture was concentrated at low pressure, and the residue was dissolved in EA (200 mL). The solution was washed with brine, dried over anhydrous MgSO₄ and evaporated at low pressure. The residue was purified by chromatography using 10% EA in PE to give 75-9 (9.9 g, 27%).

To a solution of 75-9 (6.3 g, 9.45 mmol) in CH₃CN:H₂O (3:1, 36 mL:12 mL) was added CAN (15.5 g, 28.3 mmol), and the mixture was stirred at R.T. overnight. The mixture was extracted with EA (3×50 mL). The solution was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by chromatography using 20% EA in PE to give 75-10 (3.6 g, 71%) as a white solid.

To a solution of 75-10 (2.4 g, 4.4 mmol) in anhydrous DCM (10 mL) was added slowly BCl₃ (1 N, 30 mL CH₂Cl₂) at −70° C., and the mixture was stirred for 2 h. at −70° C. The mixture was quenched with the slow addition of MeOH at −70° C., and the mixture was concentrated at low pressure. The residue was purified by chromatography using 50% EA in PE to give 75-11 (1.2 g, 86%) as a white solid. ESI-MS: m/z 277.1 [M+H]⁺.

To a solution of PPh₃ (3.37 g, 12.8 mmol) in pyridine (15 mL) was added I₂ (3.06 g, 12 mmol) at 0° C., and the mixture was stirred at R.T. for 30-40 mins. The mixture was cooled to 0° C., and then treated with 75-11 (2.2 g, 8 mmol) in Py. (5 mL). The mixture was stirred at R.T. under N₂ for 12 h. The mixture was quenched with sat. Na₂S₂O₃ (aq.) and extracted with CH₂Cl₂ (3×50 mL). The organic phase was dried over anhydrous MgSO₄, and then concentrated at low pressure. The residue was purified by chromatography using 1-2% MeOH in CH₂Cl₂ to yield 75-12 (1.8 g, 58%) as a white solid.

To a solution of 75-12 (1.35 g, 3.5 mmol) in THF:CH₃CN (10 mL:5 mL) was added DBU (1.06 g, 7 mmol), and the mixture was stirred at 60-70° C. for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL). The solution was washed with 10% HCl solution and brine. The organic phase was dried over anhydrous MgSO₄ and concentrated at low pressure. The residue was purified by chromatography using 30% EA in PE to give 75-13 (0.5 g, 55%).

To a solution of 75-13 (670 mg, 2.6 mmol) in CH₃CN (6 mL) was added NIS (730 mg, 3.25 mmol) and 3HF.TEA (335 mg, 2.1 mmol) at 0° C., and the mixture was stirred at R.T. for 2 h. The mixture was quenched with sat. NaHCO₃ (aq.) and Na₂S₂O₃ (aq.) solution. The mixture was extracted with EA (3×20 mL), dried over anhydrous MgSO₄ and concentrated at low pressure. The residue was purified by chromatography using 1-2% MeOH in CH₂Cl₂ to give 75-14 (1.2 g, 80%).

To a solution of 75-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) and TEA (0.75 g, 7.42 mmol) in DCM (10 mL) was added BzCl (1.15 g, 8.16 mmol) in DCM (1 mL) at 0° C., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ (10 mL), and then washed with HCl (0.1 N, 20 mL) solution and brine. The organic phase was dried over anhydrous MgSO₄, and concentrated at low pressure. The residue was purified by chromatography using 20% EA in PE to afford 75-15 (850 mg, purity-80%).

To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa (1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture was stirred at 90-100° C. for 24 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL), and washed with brine. The organic phase was dried over anhydrous MgSO₄, and then concentrated at low pressure. The residue was purified by chromatography using 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam.

Compound 75-16 (250 mg, 0.41 mmol) was treated with NH₃.MeOH (7 N, 5 mL), and the mixture stirred at R.T. for 15 h. The mixture was concentrated at low pressure, and the residue was purified by prep-HPLC to give compound 75 (33 mg, 25%) as a white solid. ESI-MS: m/z 295.1 [M+H]⁺.

Example 47 Compound 73

To a solution of IBX (133.33 g, 476 mmol) in dry CH₃CN (2 L) was added 73-1 (100.0 g, 216 mol) at R.T. The mixture was refluxed and stirred for 12 h. The mixture was filtered, and the filtrate was concentrated at low pressure to give 73-2 as a yellow oil (90.0 g, 90.4%).

Compound 73-2 (50.0 g, 108.70 mmol) was coevaporated with anhydrous toluene twice to remove H₂O. Ethynyl magnesium bromide, (800 mL, 400.0 mmol) was added dropwise into a solution of 73-2 in THF (500 mL) over 20 mins at −78° C. The mixture was stirred for about 10 mins at −78° C. When the starting material was consumed, the ice-acetone cooling bath was removed. The mixture was quenched with a sat. NH₄Cl solution with stirring, and then warmed to R.T. The mixture was extracted with EA, filtered through Celite and washed with brine. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure to give crude 73-3 as a deep yellow oil (48.0 g, yield: 90.8%).

Compound 73-3 (200.0 g, 411.52 mmol) was dissolved in anhydrous CH₂Cl₂ (2000 mL) and then DMAP (100.41 g, 823.05 mmol) and Et₃N (124.94 g, 1.23 mol) were added at R.T. The mixture was treated with benzoyl chloride (173.46 g, 1.23 mol) at 0° C. After stirring for 12 h at R.T., the reaction was quenched with H₂O. The combined aq. phase was extracted with DCM. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and evaporated to dryness under reduced pressure to give a black oil. The oil was purified by column chromatography using 7%-20% EA in PE as the eluent to give a yellow oil. The residue triturated with CH₃OH and filtered. The filter cake was concentrated in vacuo to give 73-4 as a white solid (30.0 g, 36.4%).

Uracil (34.17 g, 305.08 mmol) were coevaporated with anhydrous toluene twice to remove H₂O. To a stirred suspension of uracil in anhydrous MeCN (150 mL) was added N,O-BSA (123.86 g, 610.17 mmol) at R.T. The mixture was refluxed for 1.5 h and then cooled to R.T. Compound 73-4 (90 g, 152.54 mmol, which were coevaporated with anhydrous toluene twice to remove H₂O) was added. TMSOTf (237.05 g, 1.07 mol) was then added at R.T. The mixture was heated to 70° C., and then stirred overnight and then monitored by LCMS. The mixture was cooled to R.T., and quenched with a sat. NaHCO₃ solution. The solution was extracted with EA. The organic layer was dried over Na₂SO₄, and then concentrated at low pressure. The residue was purified using a silica gel column eluted with 10%-50% EA in PE to give 73-5 as a white solid (45 g, 50.9%).

Compound 73-5 (50 g, 86.21 mmol) was treated with NH₃ in MeOH (1 L) at R.T., and then stirred for 48 h. The mixture was concentrated at low pressure, and the residue was purified by column chromatography (10% MeOH in DCM) to give 73-6 (12.6 g, 54.55%) as a white solid.

To a solution of cyclopentanone (100 g, 1.189 mmol) and trimethyl orthoformate (150 mL) in MeOH (600 mL) was added TsOH.H₂O (1.13 g, 5.9 mmol), and the mixture was stirred at R.T. for 30 mins. The reaction was quenched with NaOMe (0.32 g, 5.9 mmol) and H₂O, and the solution was extracted by n-hexane. The organic layer was dried over anhydrous Na₂SO₄, and then concentrated at low pressure. The cyclopentyl dimethoxy acetal and 73-6 (20 g, 74.63 mmol) was dissolved in DCE (200 mL), and then treated with TsOH.H₂O (0.71 g, 3.73 mmol). The mixture was stirred at 50° C. for 12 h, and then concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 73-7 (15.4 g, 61.8%) as a white solid.

Compound 73-7 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine three times to remove H₂O. To an ice-cold solution of 73-7 in anhydrous pyridine (100 ml) was added TsCl (22.8 g, 0.12 mol) at 0° C., and the mixture was stirred overnight and monitored by LCMS and TLC. The reaction was quenched with H₂O and extracted with EA. The organic phase was dried over anhydrous NaSO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 78-8 (20.0 g, 69.0%) as a white solid.

To a solution of 73-8 (20.0 g, 0.04 mol) in acetone (200 ml) was added NaI (31.0 g, 0.2 mol) and heated to reflux overnight and monitored by LCMS. The mixture was quenched with a sat. Na₂S₂O₃ solution, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 73-9 (15.0 g, 83.3%) as a white solid.

To 73-9 (30.0 g, 0.068 mol) in dioxane (60 mL) in sealed tube was added CuBr (4.9 g, 0.034 mol), i-Pr₂NH (13.6 g, 0.135 mol) and (CH₂O)_(n)(5.1 g, 0.17 mol) under N₂. The mixture was heated at reflux for 16 h. The mixture was diluted with EtOAc, and washed with a sat. NH₄Cl solution and brine. The solution was dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=100:1 to 15:1) to give 73-10 (10.0 g, 32.3%) as a white solid.

Compound 73-10 (10 g, 21.83 mmol) was treated with HCOOH (80%) in H₂O at R.T. The solution was stirred at 60° C. for 2 h, and then concentrated at a low pressure. The residue was purified by column chromatography (1%-10% MeOH in DCM) to give 73-11 (5.1 g, 58.55%) as a white solid.

Compound 73-11 (5 g, 12.79 mmol) was dissolved in anhydrous MeOH (100 mL) and treated with NaOMe (4.83 g, 89.5 mmol) at R.T. The solution was stirred at 60° C. for 36 h. The mixture was quenched with CO₂ and then concentrated at low pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give 73-12 (2.3 g, 68.05%) as a yellow solid. ¹H-NMR (CDCl₃, 400 MHz) δ=7.29 (d, J=8 Hz 1H), 6.10 (s, 1H), 5.71 (d, J=8.0 Hz 1H), 5.18 (t, J=6.4 Hz, 1H), 4.79-4.84 (m, 1H), 4.61 (d, J=8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).

To an ice-cold solution of 73-12 (1.5 g, 5.68 mmol) in anhydrous MeCN (15 mL) was added NIS (1.66 g, 7.39 mmol) and TEA.3HF (0.73 g, 4.55 mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reaction was quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH in DCM) to give 73-13 (1.08 g, 46.2%) as a yellow solid.

To a stirred solution of 73-13 (1 g, 2.44 mmol) in anhydrous DCM (10 mL) was added DMAP (0.60 g, 4.88 mmol) and Et₃N (0.74 g, 7.32 mmol) at R.T. The mixture was treated with benzoyl chloride (0.79 g, 5.61 mmol) at 0° C. and then stirred at R.T. for 3 h. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography (0-10% MeOH in DCM) to give 73-14 (0.9 g, 59.6%) as a white solid.

Bu₄NOH (55% in H₂O, 13.74 mL) was treated with TFA (to adjust pH=3-4). The mixture was cooled to R.T. To a solution of 73-14 (0.9 g, 1.46 mmol) in DCM (9 mL) was added m-CPBA (80%, 1.57 g, 7.28 mmol) at R.T. The mixture was stirred at 25° C. for 48 h. The mixture was washed with sat. aq. NaHCO₃. The organic layer was passed through an anhydrous Al₂O₃ column, and the solution was concentrated at low pressure. The residue was purified by a silica gel column (30% EA in PE) to give 73-15 (0.26 g, 35.1%) as a yellow solid.

Compound 73-15 (0.25 g, 0.49 mmol) was dissolved in NH₃/MeOH (5 mL, 7 M), and the mixture was stirred at R.T. for 24 h under N₂. The mixture was concentrated at low pressure at R.T., and the residue was purified by a silica gel column (5% MeOH in DCM) to give 73-16 (100 g, 67.75%) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=7.83 (d, J=8 Hz 1H), 6.29 (s, 1H), 5.67 (d, J=6.0 Hz 1H), 5.12 (t, J=6.8 Hz, 1H), 4.99-5.01 (m, 1H), 4.38 (d, J=19.6 Hz 1H), 3.74-3.81 (m, 2H), 3.35 (s, 1H).

Compound 73-16 (100 mg, 0.33 mmol) was co-evaporated with toluene three times to remove H₂O. To a stirred solution of 73-16 (100 mg, 0.33 mmol) in a mixture of MeCN (1.0 mL) and NMI (271 mg, 3.3 mmol) was added a solution of 73-C (216.5 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then reaction was quenched with water. The mixture was diluted with EA (20 mL), and the organic layer was washed with water and brine, and dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure, and the residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product. The crude product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 73 (35.6 mg, 19.0%) as a white solid. ESI-LCMS: m/z 592 [M+Na]⁺.

To a stirred solution of 73-A (2.0 g, 13.16 mmol) and phenol (1.22 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was warmed gradually to R.T., and then stirred for 2 h. The solution was re-cooled to −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed by the dropwise addition of TEA (2.66 g, 26.29 mmol) in DCM (20 mL). The mixture was warmed gradually to R.T., and then stirred for 2 h. The organic solvent was removed at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 73-C (0.9 g, 22.3%) as a colorless oil.

Example 48 Compound 66

Compound 66-2 (2648 g, 7.3 mol) was dissolved in anhydrous dichloromethane (10 L), and the solution was cooled to −40° C. with stirring under N₂. Compound 66-1 (1 kg, 7.69 mol) was dissolved in anhydrous CH₂Cl₂ (3 L) and added to the solution of 66-2 over 30 mins at −40° C. The stirred mixture was allowed to warm to R.T. overnight. The mixture was concentrated under reduced pressure to dryness, and the residue was suspended in TMBE (6 L). The suspension was filtered to remove Ph₃PO, and the filtrate was concentrated under reduced pressure to afford crude 66-3 (1230 g, 78.6%). ¹H NMR (400 Hz) (CDCl₃): δ 6.65 (dt, J=7.6 Hz, 1H), 4.82 (dd, J=14.8, 7.6 Hz, 1H), 4.20-4.10 (m, 3H), 3.59 (t, J=8.0 Hz, 1H), 1.86 (d, J=1.2 Hz, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.26 (t, J=6.8 Hz, 3H).

Crude 66-3 (1230 g, 5.74 mol) was dissolved in acetone (30 L) at 0-5° C. KMnO₄ (1107 g, 5.17 mol) was added in one portion. After being stirred at 0-5° C. for 5 h, the reaction was quenched with sat. aq. sodium sulfite (20 L). After 30 mins, a colorless suspension was formed. The solid was removed by filtration and washed with EA (6 L). The filtrate was extracted with EA (3×2 L). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid residue. The residue was dissolved in EA, and PE was added to give a precipitate. The solid was collected by filtration and recrystallization was 3 times to give 66-4 (770 g, 53.6%) as a white solid.

To a stirred solution of 66-4 (770 g, 3.1 mol) in anhydrous DCM (5 L) and triethylamine (1.1 L, 8.05 mol) at 0° C. was added slowly sulfuryl chloride (300 mL, 3.6 mmol). The mixture was stirred at R. T. for 2 h, diluted with DCM (3 L), and washed with sat. NaHCO₃ aq. and brine. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column using PE:EA=1:0 to 10:1 as the eluent to give 66-5 (490 g, 50.6%) as an oil.

Tetraethylammonium fluoride hydrate (650 g, 3.7 mol) was added into a solution of 66-5 (490 g, 1.6 mol) in anhydrous dioxane (3 L), and the mixture was heated to 120° C. for 16 h. The mixture was then cooled to ambient temperature. 2,2-Dimethoxypropane (3 L) was added followed by conc. aq hydrochloric acid (200 mL). The mixture was stirred for 3 h at ambient temperature. The solvent was concentrated to ⅓ of the original volume, and then diluted with EA (3 L). The mixture was washed with cold sat. aq. sodium bicarbonate and brine. The combined aqueous layer was back-extracted with EA (1 L). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated at low pressure to give crude 66-6 (220 g, 70.8%).

Crude 66-6 (220 g, 0.89 mol) was dissolved in ethanol (2 L) and conc. aq. HCl (60 mL). The solution was stirred at ambient temperature for 48 h. and then concentrated under reduced pressure followed by co-evaporations with toluene 3 times to give 66-7 as a pale yellow solid (110 g).

Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoyl chloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture was stirred at ambient temperature for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.

To a solution of 66-8 (100 g, 269 mmol) in anhydrous THF (1000 ml) was added dropwise a solution of lithium tri-tert-butoxyaluminohydride (400 ml, 1M, 0.4 mol) at −78° C. under N₂ for 30 mins. The solution was stirred at −20° C. for 1 h, and TLC (PE:EA=3:1) showed that the reaction was complete. The mixture was quenched with sat.NH₄Cl, and diluted with EA. After filtration, the filtrate was extracted with EA. The combined layers were dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by a silica column gel (PE:EA=20:1) to give 66-9 (100 g, 100%) as a colorless oil.

To a stirred solution of PPh₃ (140 g, 382 mol) in CH₂Cl₂ (1000 ml) was added 66-9 (100 g, 269 mmol) at −20° C. under N₂. After stirring for 15 mins, CBr₄ (177 g, 382 mol) was added dropwise while maintaining the temperature between −25 and −20° C. under N₂. The mixture was stirred below −17° C. for 20 mins. Silica gel was added to the mixture. The mixture was filtered through cold silica column gel and washed with PE:EA (50:1 to 4:1). The combined filtrates were concentrated under reduced pressure at R.T. to give the crude oil product. The residue was purified by a silica column gel a second time (PE:EA=50:1 to 4:1) to give 66-10 (α-isomer, 64 g, yield: 55%) as a colorless oil.

A mixture of 6-chloro-guanine (55.8 g, 316.5 mol) and t-BuOK (39.5 g, 352.7 mmol) in t-BuOH (500 mL) and MeCN (280 mL) was stirred for 30 mins. Compound 66-10 (48 g, 105.5 mmol) was added at R.T., and the mixture was heated to 50° C. and stirred overnight. The reaction was monitored by TLC (PE:EA=2:1). The mixture was quenched with solid NH₄Cl. After stirring for 1 h, the mixture was filtered and washed with MeCN. The filtrate was evaporated at low pressure, and the residue was purified by a silica gel column to give 66-11 (33 g, 57%).

To a solution of 66-11 (49 g, 93.1 mol) in CH₂Cl₂ (200 mL) was added AgNO₃ (31.7 g, 186 mmol), collidine (22.5 g, 186 mmol) and MMTrCl (43 g, 140 mmol) in small portions under N₂ at 0° C. The mixture was stirred at R.T., and monitored by TLC (PE:EA=4:1). After filtration, the organic phase was washed with NaHCO₃ aqueous and brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column (PE:ME=20:1 to 1:1) to give 66-12 (70 g, 94.2%).

Sodium (10.1 g, 439 mmol) was dissolved in dry EtOH (600 mL) at 70° C. and then cooled to 0° C. To a solution of 66-12 (70 g, 87.7 mmol) was added a freshly prepared NaOEt solution in portions at 0° C., and the mixture was stirred for 1 h. at R.T. After TLC and LCMS showed the reaction was completed, the reaction was quenched with carbon dioxide. The mixture was evaporated at low pressure, and the residue was purified using silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give 66-13 (50 g, yield 5%) as a yellow solid.

A mixture of PPh₃ (35 g, 133.5 mol) and I₂ (31.75 g, 125 mmol) in anhydrous pyridine (600 mL) was stirred for 30 mins, and then a solution of 66-13 (50 g, 83.3 mmol) in pyridine (100 mL) was added at 0° C. The mixture was stirred overnight at R.T. and monitored by TLC (DCM:MeOH=50:1). The reaction was quenched with a sat. NaHCO₃ solution, and extracted with DCM (3×50 mL). The organic phase was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (DCM:MeOH=200:1 to 50:1) to give 66-14 (50 g, 84.7%).

To a solution of 66-14 (37 g, 52.1 mmol) in dry THF (400 mL) was added DBU (16 g, 105 mmol). The mixture was heated to reflux and stirred for 3 h. The reaction was monitored by LCMS. The reaction was quenched with a sat. NaHCO₃ solution, and extracted with EA. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE:EA=10:1 to 5:1) to give 66-15 (25 g, 61.1%) as a white solid.

To an ice-cold solution of 66-15 (26 g, 44.6 mmol) in dry MeCN (300 mL) was added NIS (12.68 g, 56 mmol) and NEt₃.3HF (10.6 g, 67 mmol) at 0° C. The reaction was stirred at R.T. for 2 h. and monitored by LCMS. After the reaction was completed, the reaction was quenched with a sat Na₂SO₃ and sat. NaHCO₃ solution, and extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE:EA=8:1 to 1:1) to give 66-16 (21 g, 64.4%) as a white solid.

To a solution of 66-16 (21 g, 28.8 mol) in CH₂Cl₂ (150 mL) was added AgNO₃ (9.8 g, 59.6 mmol) and collidine (7 g, 59.8 mmol) and MMTrCl (13.1 g, 42.5 mmol) in small portions under N₂ at 0° C. The mixture was stirred at R.T., and the reaction was monitored by TLC (PE:EA=2:1). After filtration, the solution was washed with sat. aq. NaHCO₃ and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column to give 66-17 (25 g, yield 86.5%).

To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was added NaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and the mixture was stirred for 72 h. at 95° C. The mixture was diluted with EA, washed with water and brine, and dried over MgSO₄. The organic layer was evaporated at low pressure, and the residue was purified using a silica gel column chromatography to give 66-18 (15 g, 68.8%) as a white solid.

Compound 66-18 (15.2 g, 15.3 mmol) was co-evaporated with anhydrous toluene 3 times to remove H₂O. The compound was treated with NH₃ in MeOH (7 N, 200 mL) at R.T. The mixture was stirred for 18 h at R.T., and the reaction was monitored by LCMS. The residue was concentrated at low pressure, and purified using silica gel column chromatography to give 66-19 (11 g, 81%) as a white solid.

To a stirred solution of 66-20 (14 g, 15.73 mmol) in anhydrous CH₃CN (150 mL) was added N-methylimidazole (23.5 g, 283.9 mmol) at 0 to 5° C. (ice/water bath) followed by a solution of phenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (16.33 g, 47.2 mmol, dissolved in 50 mL of CH₃CN). The solution was stirred at 0 to 5° C. for 12 h and then diluted with EA. The solution was washed 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated at low pressure, and the residue was purified on silica gel with PE:EA=5:1 as the eluent to give 66-20 (17.62 g, 93.4%) as a white solid.

Compound 66-20 (17.62 g, 14.7 mmol) was dissolved in 80% AcOH (200 mL), and the mixture was stirred overnight at R.T. After removal of the solvents, the reside was purified on silica gel using PE:EA=2:1 to eluent to give the crude product, which was purified on via reverse-phase HPLC using acetonitrile and water to give compound 66 (5.25 g, yield 66%) as a white solid. ESI-LCMS: m/z 655 [M+H]⁺.

Example 49 Compound 67

To a solution of the nucleoside (300 mg, 1.09 mmol) and proton-sponge (467 mg, 2.18 mmol) in anhydrous CH₃CN (5 mL) at 0° C. under N₂ was added dropwise a solution of phosphorus oxychloride (330 mg, 2.18 mmol) in anhydrous CH₃CN (1 mL). The mixture was stirred at 0° C. for 30 mins, and the hydrogen chloride salt of (S)-ethyl 2-aminopropanoate (998 mg, 6.52 mmol) and triethylamine (1.5 mL, 10.87 mmol) at 0° C. were added. The mixture was stirred overnight at 30° C. The reaction was quenched with water, and extracted with EA (3×20 mL). The organic layer was concentrated at low pressure, and the residue was purified by reverse phase HPLC to give compound 67 (20 mg, 3%) as a white solid. ESI-LCMS: m/z 535 [M−F]⁺.

Example 50 Compound 59

To a solution of sodium hydrosulfide (4.26 g, 76.0 mmol) in EtOH (100 mL) was added t-butyryl chloride (76.2 mmol; 9.35 mL) dropwise at 0° C., and the mixture was stirred at R.T. for 1 h. A solution of 2-(2-chloroethoxy)ethanol (57 mmol; 6.0 mL) and TEA (21 mL, 120 mmol) was added, and the mixture was heated at reflux for 60 h. The mixture was filtered, and then concentrated to a small volume. The residue was dissolved in EA, and then washed with water, sat. aq. NaHCO₃ and brine. The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (10.0 g) was isolated and 5 grams were purified by silica gel flash column chromatography using a gradient of 0 to 100% EA in hexane to give 59-3 (4.5 g, 22 mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.74 (m, 2H), 3.5-3.65 (m, 4H), 3.1 (t, 2H), 1.25 (s, 9H).

A solution 59-3 (4.5 g; 21.8 mmol) and triethylamine (6.7 mL, 87.2 mmol) in tetrahydrofuran (50 mL) was added dropwise over 1 h to a stirred solution of N,N-diisopropylphosphorodichloridite (2.0 mL, 10.9 mmol) in THF (50 mL) under argon at −78° C. The mixture was stirred at R.T. for 2 h, and then diluted with EA (200 mL). The mixture was washed with sat. aq. NaCl and dried over Na₂SO₄. After filtration, the filtrate was evaporated under reduced pressure to give a pale yellow oil. Purification by flash column chromatography using a gradient of EA (0-5%) in hexane containing 5% triethylamine afforded 59-4 (2.5 g, 4.25 mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.82 (m, 4H), 3.57-3.65 (m, 10H), 3.1 (t, 4H), 1.25 (s, 18H), 1.17 (t, 12H); ³¹P-NMR (CDCl₃): 148.0 ppm.

Compound 59-5 (285 mg, 0.9 mmol) and DCI (175 mg, 1.5 mmol) were coevaporated twice with ACN and then dissolved in ACN (5 mL). Compound 59-4 (790 mg, 1.35 mmol) in ACN (4 mL) was added, and the reaction was monitored by TLC. After 15 mins, tert-butylhydroperoxide (0.5 mL of 5.5M solution in decane) was added, and the mixture was stirred for 10 mins. The mixture was diluted with EA (25 mL), washed with sat. aq. NaHCO₃ and sat. aq. NaCl solution, dried over Na₂SO₄, filtered and concentrated. Purification by flash column chromatography using a gradient of EA (0-100%) in hexane afforded 59-6 (0.17 g, 0.22 mmol) as a white solid. Compound 59-6 was dissolved in 80% aq. HCOOH (5 mL). After 30 mins at R.T., the solvent was removed and coevaporated twice with toluene. The residue was dissolved in methanol (10 mL) and TEA (0.2 mL) was added. After 2 mins at R.T., the solvent was removed in vacuo. Purification by flash column chromatography using a gradient of methanol (0-15%) in DCM afforded compound 59 (90 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.70-3.82 (m, 4H), 3.57-3.65 (m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.55 ppm.

Example 51 Compound 60

Compound 60-1 (6.0 g, 31.6 mmol) was prepared using a similar procedure to the one used to prepared 59-3 using 4-chlorobutanol. Compound 60-1 was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (s, 2H), 2.86 (m, 2H), 1.65 (m, 4H), 1.25 (s, 9H).

Compound 60-2 (2.14 g, 4.0 mmol) was prepared using a similar procedure to the one used to prepared 59-4. Compound 60-2 was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H), 1.25 (s, 18H), 1.17 (t, 12H). ³¹P-NMR (CDCl₃): 143.7 ppm.

Compound 60-3 (0.23 g, 0.22 mmol) was prepared using a similar procedure to the one used to prepared 59-6 using 59-5 and 60-2. Compound 60-3 was obtained as a white solid. Using a similar procedure to the one used to prepared compound 59, 60-3 was used to prepare compound 60 (170 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.56 ppm.

Example 52 Compound 58

Compound 58-1 was prepared according to the procedure described in Lefebre et al. J. Med. Chem. (1995) 38:3941-3950, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 58-1.

Compound 58-2 (0.33 g, 0.5 mmol) was prepared using a similar procedure to the one used to prepared 59-6 using 59-5 and 58-1. Compound 58-2 was obtained as a white solid. Using a similar procedure to the one used to prepared compound 59, 58-2 was used to prepare compound 58 (130 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.2 (t, 4H), 1.69 (s, 4H), 1.3 (s, 3H), 1.23 (s, 18H); ³¹P-NMR (CDCl₃): −2.4 ppm.

Example 53 Compound 47

Compound 47-1 (1.0 g, 3.53 mmol) was coevaporated with anhydrous pyridine 3 times to remove H₂O. To an ice-cold solution of 47-1 in anhydrous pyridine (9 mL) was added TsCl (808 mg, 4.24 mmol) in pyridine (3 mL) drop-wise at 0° C., and the mixture was stirred for 18 h. at 0° C. The reaction was monitored by LCMS, and then quenched with H₂O. After concentration at low pressure, the residue was dissolved in EA (50 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-2 (980 mg, 63%) as a white solid.

To a solution of 47-2 (980 mg, 2.24 mmol) in acetone (10 mL) was added NaI (1.01 g, 6.73 mmol), and the mixture was heated to reflux overnight. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated at low pressure. The residue was dissolved in EA (50 mL). The solution was washed with brine, and dried over anhydrous Na₂SO₄. The solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-3 (700 mg, 79%) as a solid.

To a solution of 47-3 (700 mg, 1.78 mmol) in dry THF (9 mL) was added DBU (817 mg, 5.34 mmol), and the mixture was heated to 60° C. The mixture was stirred overnight, and monitored by LCMS. The reaction was quenched with sat. NaHCO₃ and extracted with EA (3×50 mL). The organic phase was dried over anhydrous Na₂SO₄, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-4 (250 mg, 53%) as a white solid.

To an ice-clod solution of 47-4 (250 mg, 0.94 mmol) in dry MeCN (5 mL) was added NEt₃.3HF (151 mg, 0.94 mmol) and NIS (255 mg, 1.13 mmol). The mixture was stirred at R.T., for 3 h., and checked by LCMS. The reaction was quenched with sat Na₂S₂O₃ and sat. NaHCO₃ solution, and extracted with EA (3×50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (2% acetone in DCM) to give 47-5 (170 mg, 44%).

To a solution of 47-5 (270 mg, 0.65 mmol) in dry DCM (4 mL) was added DMAP (158.6 mg, 1.3 mmol), and BzCl (137 mg, 0.98 mmol). The mixture was stirred for 4-5 h. at R.T., and checked by LCMS. The mixture was diluted with CH₂Cl₂, and washed with sat. NaHCO₃ solution and brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-6 (290 mg, 86%) as a solid.

To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100° C. The mixture was diluted with EA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-7 (500 mg, 56%) as a solid.

To a solution of 47-7 (500 mg, 0.98 mmol) in anhydrous CH₃CN (5 mL) was added TPSCl (741 mg, 2.45 mmol), DMAP (299.6 mg, 2.45 mmol) and NEt₃ (248 mg, 2.45 mmol) at R.T., and the mixture was stirred overnight. The mixture was then treated with NH₃ in THF (5 mL) and then stirred for another 30 mins. The mixture was diluted with EA (100 mL). The solution was washed with 0.5% AcOH solution. The organic solvent was dried over anhydrous MgSO4, and concentrated at low pressure. The crude product was purified by silica gel column chromatography (2% Acetone in DCM) to give 47-8 (257 mg, 51.6%) as a white solid. ESI-MS: m/z 509 [M+H]⁺.

Compound 47-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL). The mixture was kept overnight at R.T. and evaporated. The residue was crystallized from methanol to give compound 47 (30 mg). The mother liquor was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer to yield additional compound 47 (13 mg). Compound 47 (total yield 43 mg, 73%). MS: m/z 299.7 [M−1]⁻.

Example 54 Compound 83

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added 1-naphthol (1.88 g, 13 mmol) at −70° C., and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T. and stirred for 1 h. Crude 83-1 was obtained.

To a stirred solution of (S)-isopropyl 2-aminopropanoate hydrochloride (2.17 g, 13 mmol) in DCM (10 mL) was added crude 83-1 at −70° C. TEA (2.63 g, 26 mmol) was added to the stirred solution dropwise at −70° C. The mixture was gradually warmed to R.T. and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column (PE:MTBE=5:1˜1:1) to give pure 83-2 (1.6 g, 35%).

To a solution of 83-(A) (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol) in anhydrous CH₃CN (4 mL) was added 83-2 (240 mg, 0.674 mol, in DCM (5 mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS. The reaction was quenched with water, and extracted with CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by sil-gel (PE:EA=5:1˜2:1) to give 83-3 (380 mg, 93%).

Compound 83-3 (380 mg, 0.314 mmol) was dissolved in CH₃COOH (80%, 8 mL), and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS. The mixture was concentrated at low pressure, and the residue was purified by chromatography (PE:EA=1:1˜EA) to give crude compound 83. The crude product was purified by prep-HPLC (neutral system, NH₄HCO₃) to give pure compound 83 (70 mg, 80%) as a white solid. ESI-MS: m/z 665.1 [M+H]⁺.

Example 55 Compound 79

A solution of 79-1 (16.70 g, 0.363 mol) and TEA (36.66 g, 0.363 mol) in CH₂Cl₂ (150 mL) was added dropwise to a stirred solution of POCl₃ (55.65 g, 0.363 mol) in DCM (100 mL) over 25 mins at −78° C. After the mixture was stirred for 2 h. at R.T., the triethylamine hydrochloride salt was filtered, and washed with CH₂Cl₂ (100 mL). The filtrate was concentrated at low pressure, and the residue was distilled under high vacuum (˜10 mm Hg) with a cow-head fraction collector. The product was collected between 45° C. (distillation head temperature) as a colorless liquid (30.5 g, 50% yield). ¹H-NMR (400 MHz, CDCl₃) δ=4.44 (dq, J=10.85, 7.17 Hz, 2H), 1.44-1.57 (m, 3H); ³¹P-NMR (162 MHz, CDCl₃) δ=6.75 (br. s., 1P).

To a stirred suspension of 83-A (93 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) was added TEA (61 mg, 0.15 mmol) at R.T. The mixture was cooled to −20° C., and then was treated with a 79-2 (35 mg, 0.21 mmol) solution dropwise over a period of 10 mins. The mixture was stirred at this temperature for 15 min., and then was treated with NMI (27 mg, 0.33 mmol). The mixture was stirred at −20° C., and then slowly warmed to R.T. The mixture was stirred overnight. The mixture was suspended in EA (15 mL), washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated at low pressure, and the residue was purified by chromatography (DCM:MeOH=100:1) to give 79-3 (60 mg, yield: 56%) as a solid.

A solution of 79-3 (60 mg, 0.085 mmol) in 80% AcOH aqueous (2 mL) was stirred at R.T. for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column eluting DCM/MeOH=50/1 and prep-HPLC to give compound 79 (23 mg, 62%) as a white solid. ESI-MS: m/z 436.3 [M+H]⁺.

Example 56 Compound 80

Compound 80-2 was prepared using a similar procedure as for the preparation of 79-2 using a solution of iso-butanol (23.9 g, 322.98 mmol) and POCl₃ (49.5 g, 322.98 mmol). Compound 80-2 (26 g, 42% yield) was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.10 (dd, J=9.04, 6.39 Hz, 2H), 2.09 (dq, J=13.24, 6.67, 6.67, 6.67, 6.67 Hz, 1H), 1.01 (d, J=6.62 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=7.06 (br. s., 1P).

To a stirred suspension of 83-A (310 mg, 0.5 mmol) in CH₂Cl₂ (3 mL) was added TEA (202 mg, 2 mmol) at R.T. The mixture was cooled to −20° C., and then was treated with 80-2 (134 mg, 0.7 mmol). The mixture was stirred at this temperature for 15 mins and then was treated with NMI (90 mg, 1.1 mmol). The mixture was stirred at −20° C. for 1 h., and then slowly warmed to R.T. overnight. The mixture was suspended in EA (15 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated at low pressure, and the residue was purified by silica column gel (DCM:MeOH=100:1) to give 80-3 (310 mg, yield: 84%) as a solid.

A solution of 80-3 (310 mg, 0.43 mmol) in 80% AcOH aqueous (4 mL) was stirred at R.T. for 2 h. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column eluting DCM/MeOH=50/1 and prep-HPLC to give compound 80 (79 mg, 50%) as a white solid. ESI-MS: m/z 464.0 [M+H]⁺.

Example 57 Compound 81

Compound 81-2 was prepared using a similar procedure as for the preparation of 79-2 using a solution of isopropyl alcohol (21 g, 350 mmol) and POCl₃ (53.6 g, 350 mmol). Compound 81-2 (40.5 g, 65% yield) was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.94-5.10 (m, 1H), 1.48 (d, J=6.17 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=5.58 (br. s., 1P).

Compound 81-3 was prepared using a similar procedure as for the preparation of 80-3 using 81-2 (124 mg, 0.7 mmol) and 83-A (310 mg, 0.5 mmol). Compound 81-3 (300 mg, 83%) was obtained as a solid.

Compound 81 was prepared using a similar procedure as for the preparation of compound 80 using 81-3 (300 mg, 0.41 mmol) in 80% AcOH aqueous (4 mL). Compound 81 (80 mg, 43%) was obtained as a white solid. ESI-MS: m/z 450.0 [M+H]⁺.

Example 58 Compound 82

To an ice cooled solution of 82-1 (50 g, 204.9 mmol) in dry Py (400 mL) was added TIPDSCl (70.78 g, 225.4 mmol) dropwise. The mixture was stirred at R.T. for 16 h, and then concentrated at low pressure. The residue was purified by chromatography using 20% EA in PE to generate 82-2 (111.5 g, 100%) as a white solid.

To a solution of 82-2 (50 g, 103 mmol) in anhydrous CH₃CN (400 mL) was added IBX (43 g, 153 mmol) at R.T. The mixture was refluxed overnight and monitored by TLC (PE:EA=1:1). The precipitate was filtered off, and the filtrate was concentrated to give the crude 82-3 (50 g, 99%) as a white solid.

To a solution of trimethylsilylacetylene (20 g, 200 mmol) in anhydrous THF (400 mL) was added dropwise n-BuLi (80 mL, 200 mL) at −78° C. The mixture was stirred at −78° C. for 30 mins, and then warmed to R.T for 10 mins. Compound 82-3 (30 g, 60 mmol) in THF (100 mL) was added to the mixture dropwise at −78° C. The mixture was stirred at −78° C. for 1 h and then slowly warmed to R.T. The mixture was stirred for 20 mins, and then the reaction was quenched with a sat. NH₄Cl solution at −78° C. The mixture was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82-4 as a white solid (14 g, 50%).

Compound 82-4 (14 g, 24 mmol) was dissolved in anhydrous toluene (100 mL) under N₂ and cooled to −78° C. DAST (19 g, 120 mmol) was added dropwise at −78° C. and stirring was continued for 1.5 h. The mixture was diluted with EA and poured into a sat. NaHCO₃ solution. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-5 as a white solid (12 g, 81%).

A mixture of 82-5 (12 g, 20 mmol) and NH₄F (11 g, 30 mmol) in MeOH (150 mL) was refluxed for 2 h. After cooling to R.T, the mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 82-6 (3.1 g, 58%) as a white solid.

To a solution of 82-6 (3.1 g, 11.6 mmol) in dry Py (50 mL) was added imidazole (3.1 g, 46.4 mmol) and TBSCl (5.2 g, 34.8 mmol). The mixture was stirred at 50-60° C. for 3 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (100 mL). The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-7 as a white solid (5 g, 86%).

To a solution of 82-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL) was added CuBr (643 mg, 4.5 mmol), dicyclohexylamine (3.3 g, 18 mmol) and paraformaldehyde (675 mg, 22.5 mmol). The mixture was refluxed for 24 h and then cooled to R.T. The reaction was quenched with a sat. NH₄Cl solution. The mixture was extracted with EA (3×100 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82-8 as a white solid (2.0 g, 43%).

A mixture of 82-8 (2 g, 4 mmol) and NH₄F (2.2 g, 60 mmol) in MeOH (20 mL) was refluxed overnight. After cooling to R.T., the mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 82-9 (946 mg, 83%) as a white solid.

To a stirred suspension of 82-9 (946 mg, 3.33 mmol), PPh₃ (1.3 g, 5 mmol), imidazole (453 mg, 6.66 mmol) and pyridine (3 mL) in anhydrous THF (12 mL) was added a solution of I₂ (1 g, 4.33 mmol) in THF (4 mL) dropwise at 0° C. The mixture was warmed to R.T. and stirred for 16 h. The reaction was quenched with a sat. Na₂S₂O₃ aq. solution and extracted with EA (3×60 mL). The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified on a silica gel column (2% MeOH in DCM to 5% MeOH in DCM) to afford 82-10 (2.1 g, crude) as a white solid.

To a solution of 82-10 (2.1 g, 5.3 mmol) in THF (15 mL) was added DBU (15 g, 100 mmol) and the mixture stirred for 30 mins. The mixture was diluted with EA and neutralized with acetic acid. The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (1.5% MeOH in DCM) to give 82-11 as a white solid (800 mg, 90%).

To an ice-cooled solution of 82-11 (800 mg, 3 mmol) in dry MeCN (1.5 mL) was added NEt₃.3HF (484 mg, 3 mmol) and NIS (1.68 g, 7.5 mmol). The mixture was stirred at R.T. for 30 mins., and the reaction was monitored by LCMS. The reaction was quenched with sat. Na₂S₂O₃ and sat. NaHCO₃ solution, and extracted with EA (3×50 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by a silica gel column (25% EA in PE) to afford 82-12 (850 mg, 68%) as a white solid.

To a solution of 82-12 (850 mg, 2 mmol) in dry DCM (10 mL) was added DMAP (488 mg, 4 mmol) and BzCl (422 mg, 3 mol). The mixture was stirred for 4-5 h at R.T., and the reaction was monitored by LCMS. The mixture was diluted with CH₂Cl₂ (40 mL), and washed with a sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 82-13 (900 mg, 87%) as a white foam.

Tetra-butylammonium hydroxide (21 mL as 54-56% aqueous solution, ˜42 mmol, 24 eq.) was adjusted with TFA to pH˜4 (˜3.5 mL), and the solution was treated with a solution of 82-13 (900 mg, 1.7 mmol) in DCM (21 mL). m-Cloroperbenzoic acid (2.1 g, 60-70%, ˜8.75 mmol, ˜5 eq.) was added portionwise under vigorous stirring, and the mixture was stirred overnight. The mixture was diluted with CH₂Cl₂ (30 mL), and washed with a saturated NaHCO₃ solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography in (40-70% EA in PE) to give 82-14 as an oil. The residue was purified by TLC (50% EA in PE) to give pure 82-14 (350 mg 50%).

Compound 82-14 (350 mg, 0.86 mg) was treated with 7N NH₃ in MeOH (15 mL). The mixture was stirred for 2-3 h and monitored by TLC. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% isopropanol in DCM) to give 82-15 (250 mg, 96%) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ=7.75 (d, J=7.9 Hz, 1H), 6.60-6.35 (m, 1H), 5.72 (d, J=8.2 Hz, 1H), 5.37-5.25 (m, 1H), 5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 4.59-4.29 (m, 1H), 3.87-3.70 (m, 2H).

To a stirred solution of 82-16 (3.79 g, 18 mmol) and 82-17 (3 g, 18 mmol) in anhydrous DCM (60 mL) was added with a solution of TEA (4 g, 39 mmol) in DCM (40 mL) dropwise at −78° C., and the mixture was stirred for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated to give the crude product. The residue was purified by dry column chromatography (anhydrous DCM) to give pure 82-18 as a colorless oil (3 g, 54%).

Compound 82-15 (200 mg, 0.66 mmol) was coevaporated with toluene 3 times to remove H₂O. Compound 82-15 was treated with MeCN (1.5 mL) and NMI (541 mg, 6.6 mmol). The mixture was stirred at R.T., and then 82-18 (403 mg, 1.32 mmol) in MeCN (0.5 mL) was added. The residue was purified by a silica gel column (5% iPrOH in DCM) to give the crude product, which was purified by HPLC (0.1% HCOOH in water and MeCN) to give compound 82 (33 mg, 9%). ESI-LCMS: m/z 594 [M+Na]⁺.

Example 59 Compound 84

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added 1-naphthol (1.88 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T., and stirred for 1 h. A crude solution of 84-1 was obtained.

To a stirred solution of (S)-isobutyl 2-aminopropanoate hydrochloride (2.35 g, 13 mmol) in DCM (20 mL) was added TEA (2.63 g, 26 mmol) and a crude solution of 84-1 at −70° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The solvent was evaporated at low pressure, and the residue was purified by chromatography (PE:MTBE=5:1˜1:1) to give pure 84-2 (1.8 g, 37%).

To a solution of 83-A (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol) in anhydrous CH₃CN (4 mL) was added 84-2 (249 mg, 0.674 mol, in DCM (5 mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS, and then quenched with H₂O. The mixture was extracted with CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by chromatography using PE:EA=5:1˜2:1 as the eluent to give 84-3 (360 mg, 87%).

Compound 84-3 (360 mg, 0.294 mmol) was dissolved in CH₃COOH (80%, 8 mL), and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS and then quenched with MeO. The mixture was concentrated at low pressure, and the residue was purified by chromatography using PE:EA=1:1 as the eluent to generate crude compound 84. The product purified by prep-HPLC (neutral system, NH₄HCO₃) to give compound 84 (70 mg, 75%) as a white solid. ESI-MS: m/z 679.2 [M+H]⁺.

Example 60 Compound 85

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added phenol (1.22 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T., and stirred for 1 h. A crude solution of 85-1 was obtained.

Compound 85 was prepared using a similar procedure as for the preparation of compound 84 using 85-2 (205 mg, 0.674 mol, in DCM (5 mL) obtained from (S)-isopropyl 2-aminopropanoate hydrochloride and 85-1) and 83-A (300 mg, 0.337 mmol). Compound 85 (50 mg, 74%) was obtained as a white solid. ESI-MS: m/z 615.2 [M+H]⁺.

Example 61 Compound 86

Compound 86 was prepared using a similar procedure as for the preparation of compound 84 using 86-2 (214 mg, 0.674 mol, in DCM (5 mL) obtained from (S)-isobutyl 2-aminopropanoate hydrochloride and 86-1) and 83-A (300 mg, 0.337 mmol). Compound 86 (70 mg, 87%) was obtained as a white solid. ESI-MS: m/z 629.2 [M+H]⁺.

Example 62 Compound 87

Compound 87 was prepared using a similar procedure as for the preparation of compound 84 using 87-2 (223 mg, 0.674 mol, DCM (5 mL) obtained from (S)-cyclopentyl 2-aminopropanoate hydrochloride and 87-1) and 83-A (300 mg, 0.337 mmol). Compound 87 (62 mg, 71%) was obtained as a white solid. ESI-MS: m/z 641.2 [M+H]⁺.

Example 63 Compound 88

Compound 88 was prepared using a similar procedure as for the preparation of compound 84 using 88-2 (223 mg, 0.674 mol, DCM (5 mL), obtained from (S)-3-pentyl 2-aminopropanoate hydrochloride and 88-1) and 83-A (300 mg, 0.337 mmol). Compound 88 (42 mg, 60%) was obtained as a white solid. ESI-MS: m/z 643.2 [M+H]⁺.

Example 64 Compound 89

A stirred solution of phosphoryl trichloride (1.00 g, 6.58 mmol) and 5-quinoline (955 mg, 6.58 mmol) in anhydrous DCM (50 mL) was treated with a solution of TEA (665 mg, 6.58 mmol) in DCM (10 mL) at −78° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The solution was cooled to −78° C. and then treated with (S)-neopentyl 2-aminopropanoate hydrochloride (1.28 g, 6.58 mmol). TEA (1.33 g, 13.16 mmol) was added dropwise at −78° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off, and the filtrate was concentrated at low pressure. The residue was purified by a silica gel column (pure AcOEt) to give 89-1 as colorless oil (500 mg, 20%).

To a solution of 89-2 (300 mg, 0.337 mmol) and NMI (276.6 mg, 3.37 mmol) in anhydrous CH₃CN (0.9 mL) was added 89-1 (388 mg, 1.011 mmol) in CH₃CN (0.3 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with AcOEt. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by silica gel column (33% EA in PE) to give 89-3 as a yellow powder (300 mg, 71.9%).

Compound 89-3 (300 mg, 0.243 mmol) was dissolved in 80% CH₃COOH (3 mL), and the mixture was stirred at 60° C. for 2.5 h. The mixture was partitioned between AcOEt and water. The organic layer phase was washed by brine, dried over sodium sulfate and concentrated at low pressure. The residue was purified by silica gel column (50% EA in PE) to give compound 89 as a yellow powder (81 mg, crude product). The crude product (81 mg) was purified by RP HPLC to give compound 89 as a white solid. (28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H]⁺.

Example 65 Compound 90

Compound 90-1 was prepared using a similar procedure as for the preparation of compound 89-1 using phosphoryl trichloride (2.00 g, 13.16 mmol), 1-naphthol (1.882 g, 13.16 mmol) and (S)-neopentyl 2-aminopropanoate hydrochloride (2.549 g, 13.16 mmol). Compound 90-1 (600 mg, 12%) was obtained as a colorless oil.

A solution of 90-2 (230 mg 0.26 mmol) and NMI (212 mg 2.60 mmol) in anhydrous CH₃CN (1 mL) was treated with a solution of 90-1 (300 mg 0.78 mmol) in anhydrous CH₃CN (0.5 mL) at R.T. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (3×20 mL). The organic layer was washed with brine, dried by anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) to give 90-3 (300 mg, 93%) as a white solid.

Compound 90-3 (300 mg, 0.24 mmol) was dissolved in CH₃COOH (80%, 5 mL). The mixture was stirred at 60° C. for 2.5 h. The mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) to give crude compound 90 (105 mg). The crude product was purified by HPLC (0.1% NH₄HCO₃ in water and CH₃CN) to give compound 90 (45 mg, 26%) as a white solid. ESI-LCMS: m/z 693.2 [M+H]⁺.

Example 66 Compound 91

A stirred solution of 91-1 (2.00 g, 13.99 mmol) and 91-2 (2.00 g, 13.99 mmol) in anhydrous DCM (8 mL) was treated with a solution of TEA (3.11 g, 30.8 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was stirred for 2 h. at −78° C. and then gradually warmed to R.T. The organic solvent was removed at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (dry DCM) to give 91-3 as colorless oil (1 g, 20.96%).

Compound 91-4 (260 mg, 0.29 mmol) was coevaporated with toluene 3 times to remove H₂O. Dried 91-4 was treated with MeCN (0.8 mL) and NMI (240 mg, 2.9 mmol) and then stirred for 10 mins. The mixture was treated with a solution of 91-3 (291 mg, 0.87 mmol) in MeCN (0.4 mL), and then concentrated at low pressure. The residue was purified on a silica gel column (75% EA in PE)) to give 91-5 (300 mg, 86%) as a white solid.

Compound 91-5 (300 mg, 0.25 mmol) was treated with CH₃COOH (5 mL, 80%), and stirred at 50° C. for 3 h. The mixture was diluted with EA. The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (67% EA in PE) to give crude compound 91, which was purified by HPLC. The product was dried by lyophilization to give compound 91 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H]⁺.

Example 67 Compound 77

To a solution of 1,1-dimethoxycyclopentane (19.3 g, 148.52 mmol) and 77-1 (10.0 g, 37.13 mmol) in DCE (100 mL) was added TsOH.H₂O (0.7 g, 3.71 mmol). The mixture was stirred at 50° C. for 12 h. The mixture was neutralized with Et₃N, and concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 77-2 (8.7 g, 70.1%) as a white solid.

Compound 77-2 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine 3 times to remove H₂O. To an ice-cold solution of 77-2 in anhydrous pyridine (100 mL) was added TsCl (22.8 g, 0.12 mol) at 0° C., and the mixture was stirred overnight. The reaction was monitored by LCMS and TLC. The reaction was quenched with H₂O, and the mixture extracted with EA (3×200 mL). The solution was dried over anhydrous Na₂SO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 77-3 (20.0 g, 69.0%) as a white solid.

To a solution of 77-3 (20.0 g, 0.04 mol) in acetone (200 mL) was added NaI (31.0 g, 0.2 mol), and the mixture was heated to reflux overnight. The reaction was monitored by LCMS. The reaction was quenched with a sat. Na₂S₂O₃ solution. The solution was extracted with EA (3×200 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 77-4 (15.0 g, 83.3%) as a white solid.

Compound 77-4 (13.4 g, 30.16 mmol) was treated with HCOOH (80%) in H₂O at R.T. The solution was stirred at 60° C. for 2 h. The mixture was concentrated at low pressure. The residue was purified by column chromatography (1%-10% MeOH in DCM) to give 77-5 (9.1 g, 80.0%) as a white solid.

To a solution of 77-5 (5.0 g, 13.22 mmol) in anhydrous CH₃CN/THF (50 mL, 1:1, v:v) was added DBU (6.0 g, 39.66 mmol) at R.T. The solution was stirred at 50° C. for 1.5 h. The reaction was quenched with HCOOH at 0° C., and then concentrated at low pressure. The residue was purified by column chromatography (50%-70% EA in PE) to give 77-6 (3.3 g, 48.1%) as a white solid.

To an ice-cold solution of 77-6 (2.1 g, 8.39 mmol) in anhydrous MeCN (21 mL) was added NIS (2.4 g, 10.49 mmol) and TEA.3HF (1.0 g, 6.29 mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reaction was quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (30%-50% EA in PE) to give 77-7 (1.3 g, 39.3%) as a light yellow solid.

To a stirred solution of 77-7 (3.2 g, 8.08 mmol) in anhydrous DCM (32 mL) was added DMAP (2.5 g, 20.20 mmol) and Et₃N (2.5 g, 24.24 mmol) at R.T. The mixture was treated with BzCl (3.7 g, 26.66 mmol) at 0° C. and then stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography (20%-30% EA in PE) to give 77-8 (1.8 g, 31.6%) as a white solid.

Bu₄NOH (8.0 g, 13.74 mL, 55% in H₂O) was adjusted to pH=3-4 with TFA, and then cooled to R.T. To a solution of 77-8 (600 mg, 0.85 mmol) in DCM (10 mL) was added the Bu₄NOH solution and m-CPBA (917 mg, 4.25 mmol, 80%) at R.T. The mixture was stirred at 25° C. for 48 h and then washed with a sat. NaHCO₃ solution. The organic layer was directly passed through basic Al₂O₃ column, and the solvent was concentrated at low pressure. The residue was purified by a silica gel column (20%-30% EA in PE) to give 77-9 (123 mg, 24.3%) as a white solid.

To a solution of 77-9 (300 mg, 0.50 mmol) in EA/hexane (20 mL, 1:1, v:v) was added Lindlar catalyst (200 mg) under N₂. The mixture was stirred under H₂ (40 Psi) at 2° C. for 1.5 h. The suspension was filtered, and the filtrate was treated with Lindlar catalyst (200 mg) under N₂, and stirred under H₂ (40 Psi) at 25° C. for 1.5 h. The mixture was filtered, and the filtrate was concentrated at low pressure to give crude 77-10 (287 mg) as a white solid.

Compound 77-10 (287 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7 M). The mixture was stirred at R.T. for 24 h under N₂ and then concentrated at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 77-11 (50 mg, 34.7% over two steps) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=7.86 (d, J=8.0 Hz 1H), 6.26 (s, 1H), 5.62-5.86 (m, 1H), 5.49 (d, J=17.1 Hz, 1H), 5.30 (d, J=10.5 Hz, 1H), 4.41 (d, J=19.3 Hz, 1H), 3.71-3.86 (m, 1H).

Compound 77-11 (113 mg, 0.39 mmol) was co-evaporated with toluene 3 times to remove H₂O. To a stirred solution of 77-11 (113 mg, 0.39 mmol) in a mixture of MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol) was added a solution of 73-C (256 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to give crude compound 77, which purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 77 (45 mg, 20.1%) as a white solid. ESI-MS: m/z 538.2 [M−F]⁺ ESI-MS: m/z 580.2 [M+Na]⁺.

Example 68 Compound 78

To a solution of 77-9 (300 mg, 0.50 mmol) in MeOH (30 mL) was added wet Pd/C (300 mg, 10%) under N₂. The mixture was stirred under H₂ (1 atm) at 25° C. for 1.5 h. The suspension was filtered, and then concentrated at low pressure to give crude 78-1 (307 mg) as a white solid.

Compound 78-1 (307 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7 M). The mixture was stirred at R.T. for 24 h under N₂ then concentrated at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 78-2 (30 mg, 21% over two steps) as a white solid.

Compound 78-2 (91 mg, 0.31 mmol) was co-evaporated with toluene 3 times to remove H₂O. To a stirred solution of 78-2 (91 mg, 0.31 mmol) in a mixture of MeCN (0.5 mL) and NMI (254 mg, 3.90 mmol) was added a solution 73-C (203 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to the crude compound 78, which purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 78 (30 mg, 17%) as a white solid. ESI-MS: m/z 540.1 [M−F]⁺.

Example 69 Additional Compounds of Formula (I)

The foregoing syntheses are exemplary and can be used as a starting point to prepare a large number of additional compounds. Examples of compounds of Formula (I) that can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

Example 70 HCV Replicon Assay

Cells

Huh-7 cells containing the self-replicating, subgenomic HCV replicon with a stable luciferase (LUC) reporter were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 2 mM L-glutamine and supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomyocin, 1% nonessential amino acids, and 0.5 mg/mL G418.

Determination of Anti-HCV Activity

Determination of 50% inhibitory concentration (EC₅₀) of compounds in HCV replicon cells were performed by the following procedure. On the first day, 5,000 HCV replicon cells were plated per well in a 96-well plate. On the following day, test compounds were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culture media. The compounds were diluted to 10% DMSO with cell culture media, which were used to dose the HCV replicon cells in 96-well format. The final DMSO concentration was 1%. The HCV replicon cells were incubated at 37° C. for 72 h. At 72 h, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by Bright-Glo Luciferase Assay (Promega, Madison, Wis.). % Inhibition was determined for each compound concentration in relation to the control cells (untreated HCV replicon) to calculate the EC₅₀.

Compounds of Formula (I) are active in the replicon assay. The antiviral activity of exemplary compounds is shown in Table 2, where ‘A’ indicates an EC₅₀<1 μM, ‘B’ indicates an EC₅₀≥1 μM and <10 μM, and ‘C’ indicates an EC₅₀≥10 μM and <100 μM.

TABLE 2 Compound # EC₅₀ 2 A 3 A 5 A 11 A 13 B 14 A 16 A 17 A 18 A 19 A 20 A 21 A 22 A 27 C 28 A 29 C 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 40 B 41 B 42 A 43 A 49 A 51 B 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 C 60 C 61 A 62 A 66 A 67 B 70 B 73 B 77 B 79 A 80 B 81 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A

Example 71 NS5B Inhibition Assay

The enzyme activity of NS5B570-Con1 (Delta-21) was measured as an incorporation of tritiated NMP into acid-insoluble RNA products. The complementary IRES (cIRES) RNA sequence was used as a template, corresponding to 377 nucleotides from the 3′-end of HCV (−) strand RNA of the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28% Cyt, and 28% Gua. The cIRES RNA was transcribed in vitro using a T7 transcription kit (Ambion, Inc.) and purified using the Qiagen RNeasy maxi kit. HCV polymerase reactions contained 50 nM NS5B570-Con1, 50 nM cIRES RNA, about 0.5 μCi tritiated NTP, 1 μM of competing cold NTP, 20 mM NaCl, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl₂. Standard reactions were incubated for 2 h at 37° C., in the presence of increasing concentration of inhibitor. At the end of the reaction, RNA was precipitated with 10% TCA, and acid-insoluble RNA products were filtered on a size exclusion 96-well plate. After washing of the plate, scintillation liquid was added and radio labeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme-catalyzed rate was reduced by 50% (IC₅₀) was calculated by fitting the data to a non-linear regression (sigmoidal). The IC₅₀ values were derived from the mean of several independent experiments and are shown in Table 3. Compounds of Formula (I) showed activity in this assay. A value of ‘A’ in the table below indicates an IC₅₀ of <1 μM, a value of indicates an IC₅₀≥1 μM and <10 μM, and a value of ‘C’ indicates an IC₅₀ value of ≥10 μM and <100 μM.

TABLE 3 Compound # IC₅₀  6 A  7a A  7b B  9 A 12 A 15 A 26 A 28 A 38 A 44 A 46 A 50 A 63 A 64 A 69 A 76 A

Example 72 Assessment of Inhibition of Mitochondrial Function

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in patients treated with antiviral nucleoside/nucleotides. For this reason, evaluation of compounds for their potential to inhibit mitochondrial function is useful. To assess the potential for nucleotide/nucleoside analogs to interfere with normal mitochondrial functions and exhibit mitochondrial toxicity, the following were measured: (1) the ability of nucleotides to be incorporated by human mitochondrial RNA polymerase in vitro and (2) the cellular inhibition of the synthesis of the mitochondrial DNA (mtDNA)-encoded protein, cytochrome c oxidase (COX-I), relative to the nuclear DNA (nDNA)-encoded mitochondrial protein succinate dehydrogenase subunit A (SDH-A) in HepG2 cells. Control compounds and compounds of Formula (I) were studied in these assays.

Biochemical Assay

Arnold et al. “Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides” PLoS Pathog (2012) 8(11): e1003030. doi:10.1371/journal.ppat.1003030, which is hereby incorporated by reference in its entirety.

Assessment of Incorporation of Nucleotides by Human Mitochondrial RNA Polymerase (HMRP)

DdRp Assay with Human Mitochondrial RNA Polymerase

The DdRp assay with human mitochondrial RNA polymerase was performed under single turnover conditions where enzyme concentration is in excess of the primer/template. The ³³P-RNA/DNA primer/template was used at a concentration of 100 nM, together with 320 nM enzyme. The standard 10-μL reactions were carried out at 30° C. for 1 minute with 100 μM of each nucleotide 5′-triphosphate (NTP), 10 mM MgCl₂, 50 mM NaCl, 40 mM Tris, pH 7.5, and 1 mM DTT. The reaction was stopped by adding 20 μL of formamide loading dye containing 50 mM EDTA. RNA products were resolved by electrophoresis on 22.5% TBE Urea polyacrylamide sequencing gels that were scanned using a TYPHOON PhosphorImager.

Results

As shown in both FIGS. 10 and 11, the appropriate natural nucleotides were shown to be good substrates for incorporation by HMRP in each template. The template in FIG. 10 was designed to measure incorporation of UTP analogs. Primer/Template: (SEQ ID NO: 1) UUUUGCCGCGCC and (SEQ ID NO: 2) GGGAATGCTAGGCGCGGC. In the control water lanes, wherein no nucleotides were added, no incorporation was observed as indicated by the lack of product band. As shown in FIG. 10, UTP and 3′-deoxy-UTP were efficient substrates for incorporation as indicated by the prominent product band. The potential for misincorporation was assessed using the control nucleotide CTP. As provided in FIG. 10, CTP was incorporated to a lesser extent relative to UTP. In contrast to UTP and 3′-deoxy-UTP, compounds of Formula (I) and 2′-Me-2′-F-UTP were not efficient substrates for incorporation by HMRP as demonstrated by the lack of product band.

The template strand shown in FIG. 11 was designed to measure the incorporation of GTP analogs. Primer/Template: (SEQ ID NO: 3) UUUUGCCGCGCC and (SEQ ID NO: 4) GGGAATGCACGGCGCGGC. In the control water lanes, no incorporation was observed as indicated by the lack of product band. GTP and 3′-deoxy-GTP were found to be efficient substrates for incorporation as demonstrated by the significant product bands. The potential for misincorporation was assessed using the control nucleotide ATP. As shown by the lack of product band in FIG. 11, control ATP was a poor substrate for incorporation. Nucleotide analog 2′-Me-GTP (the nucleotide metabolite of monophosphate prodrug INX-0189/BMS-986094) was tested and found to be a good substrate for incorporation by HMRP as indicated by the product band. Nucleotide analog 2′-Me-2′-F-GTP (nucleotide metabolite of monophosphate prodrug GS-938) was tested and also found to be incorporated by HMRP. In contrast, compounds of Formula (I) were not efficient substrates for incorporation into the template strand by HMRP as indicated by the lack of product bands in FIG. 11.

Assessment of Inhibition of Mitochondrial Protein Synthesis—Cell Based Assay

Assay Principle

MitoBiogenesis™ In Cell ELISA kits (Cat. #MS643) were obtained from Mitosciences, OR, USA. The MitoBiogenesis™ In Cell ELISA kit is a duplexing 96 well assay that ratios both an mtDNA and an nDNA encoded mitochondrial protein. Cells were seeded in 96 microplates and after exposure to compounds for several cell doublings, the levels of the two mitochondrial proteins were measured simultaneously in each well. The two proteins assayed were each subunits of different oxidative phosphorylation enzyme complexes, one protein being subunit I of Complex IV (cytochrome c oxidase; COX I) that is mtDNA encoded and the other being the 70 kDa subunit of Complex II (succinate dehydrogenase subunit A; SDH A) that is nDNA encoded. Complex IV includes several proteins that are encoded by the mtDNA while the proteins of Complex II are entirely encoded by nDNA. To control for the density of cells present at the end of the culture period, the number of cells were assessed by staining with Janus Green and the levels of COX I/SDH A normalized to the final cell density.

96 Well Plate Assay Format for HepG2 Cells

On the first day, 1000 HepG2 cells per well were plated in a 96 well plate. On the following day, compounds to be tested were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was serially diluted (1:3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cell culture media. A 10 μL aliquot of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to dose the cells in duplicate. The final DMSO concentration was 1% (v/v). Untreated cells and wells containing no cells were included on the plate to serve as controls. Cells were then incubated with compounds and observed for 8 days at 37° C. and 5% CO₂. Plates were processed as described below in the assay procedure.

Batch Assay Format for HepG2 Cells

An alternate cell culture procedure was employed to test the potential to mediate mitochondrial toxicity at higher concentrations than achievable in the 96 well plate format. HepG2 cells were grown either in media/DMSO alone or in a series of compound concentrations in 15 cm² dishes or 6 well plates at an initial cell seeding density of 5×10⁶ and 5×10⁴ cells/mL, respectively. Cells were then incubated and observed for 8 days at 37° C. and 5% CO₂. After 8 days, the cells were harvested by trypsinization, counted, and seeded in 96 well plates at a density of 25,000 cells/well in 16 replicate wells. Cells were allowed to adhere overnight and then the plates were processed as described below in the assay procedure.

Assay Procedure

The assay was performed according to the manufacturer's instructions. Briefly, after the end of the culture period the cell culture media was gently aspirated from the wells of the plate and replaced with 100 μL of 4% (v/v) paraformaldehyde solution in phosphate buffered saline (PBS, Electron Microscopy Sciences Cat. #15713). After a 20 mins incubation at R.T., the solution was removed and the wells washed 3× with 300 μL of PBS. After the final wash, the PBS was removed and the wells overlayed with 100 μL PBS. The plates were then sealed and stored at 4° C. until used. To perform the assay, the PBS overlay was removed by blotting on a paper towel and 100 μL of 0.5% (v/v) acetic acid added to each well to block endogenous alkaline phosphatase activity. After a 5 mins incubation at R.T., the acetic acid solution was removed and the cells washed once with 200 μL PBS. Then, 100 μL of permeabilization buffer (0.1% (v/v) Triton X 100) was added to each well. After 30 mins incubation at R.T., the permeabilization buffer was removed and each well was blocked with 200 μL of 2× blocking solution for 2 h at R.T. The 2× blocking solution was then removed and 100 μL of primary antibody solution containing anti COX I and anti SDH A antibodies in 1× blocking solution was added to each well. Plates were then sealed and incubated overnight at 4° C. The primary antibody/blocking solution was removed and the plate washed 3× with 250 μL 0.05% (v/v) Tween 20 in PBS. Then, 100 μL of secondary antibody solution containing alkaline phosphatase (AP) labeled anti SDH A antibody and horseradish peroxidase (HRP) labeled anti COX I antibody was added and incubated for 1 h at R.T. The plate was then washed 4× with 250 μL 0.05% (v/v) Tween 20 in PBS. After blotting the plate dry 100 μL of AP detection reagent was added to each well, and the plate incubated in the dark for 30 mins at R.T. The optical density of each well was then measured at 405 nm. The AP detection reagent was then removed and replaced with 100 μL of HRP detection reagent, and the plate incubated in the dark for a further 30 mins at R.T. The optical density of each well was then measured at 600 nm. The HRP detection reagent was then removed and each well was then stained with 50 μL of 1× Janus Green Stain for 5 mins at R.T. After removal of the dye, the plates were washed 5× in ultrapure water to remove any remaining dye. The Janus Green stain was then solubilized by the addition of 100 μL of 0.5 M HCl and incubated for 10 mins. The optical density of each well was then measured at 595 nm.

Data Analysis

The average of all replicate background measurements from each experimental condition was calculated and subtracted from the experimental values of the same condition. The SDH A and COX I signals were then plotted as a ratio (COX I/SDH A) and normalized to the Janus Green staining intensity to correct for differences in cell density.

Results

Control compound d4T was tested and found not to inhibit mitochondrial protein synthesis at concentrations up to 100 μM as shown in FIGS. 12A-D. Control compound ddC was tested and found to strongly inhibit mitochondrial protein synthesis. See FIGS. 12A-D. As demonstrated in FIG. 12A, nucleoside monophosphate prodrug INX-08189/BMS-986094 (which delivers 2′-Me-GTP) was tested in the assay and found to strongly inhibit mitochondrial protein synthesis. In contrast, compounds of Formula (I) were tested and found to not inhibit mitochondrial protein synthesis at concentrations up to 100 μM as shown in FIGS. 12B-D.

Example 73 Combination of Compounds

Combination Testing

Two or more test compounds were tested in combination with each other using an HCV genotype 1b HCV replicon harbored in Huh7 cells with a stable luciferase (LUC) reporter. Cells were cultured under standard conditions in Dulbecco's modified Eagle's medium (DMEM; Mediatech Inc, Herndon, Va.) containing 10% heat-inactivated fetal bovine serum (FBS; Mediatech Inc, Herndon, Va.) 2 mM L-glutamine, and nonessential amino acids (JRH Biosciences). HCV replicon cells were plated in a 96-well plate at a density of 10⁴ cells per well in DMEM with 10% FBS. On the following day, the culture medium was replaced with DMEM containing either no compound as a control, the test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO, or a combination of compound 18 with one or more test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO. The cells were incubated with no compound as a control, with the test compounds, or the combination of compounds for 72 h. The direct effects of the combination of the test compounds were examined using a luciferase (LUC) based reporter as determined by the Bright-Glo Luciferase Assay (Promega, Madison, Wis.). Dose-response curves were determined for individual compounds and fixed ratio combinations of two or more test compounds.

The method utilized for evaluating combination effects used a program called MacSynergy II. MacSynergy II software was kindly provided by Dr. M. Prichard (University of Michigan). The Prichard Model allows for a three-dimensional examination of drug interactions and a calculation of the synergy volume (units: μM²%) generated from running the replicon assay using a checkerboard combination of two or more inhibitors. The volumes of synergy (positive volumes) or antagonism (negative volumes) represent the relative quantity of synergism or antagonism per change in the concentrations of the two drugs. Synergy and antagonism volumes are defined based on the Bliss independence model. In this model, synergy volumes of less than −25 indicate antagonistic interactions, volumes in the −25-25 range indicate additive behavior, volumes in the 25-100 range indicate synergistic behavior and volumes >100 indicate strong synergistic behavior. Determination of in vitro additive, synergistic and strongly synergistic behavior for combinations of compounds can be of utility in predicting therapeutic benefits for administering the combinations of compounds in vivo to infected patients.

The synergy volume results for the combinations are provided in Table 4.

TABLE 4 Combination Synergy Volume Compound (μM² %) Determination ANA-598 29.46 Synergistic (3002) HCV-796 81.72 Synergistic (3004) Ribavirin 6.77 Additive (5012) Filibuvir 23.51 Additive (3007) VX-222 32.35 Synergistic (3003) BMS-790052 38.01 Synergistic (4001) VX-950 32.28 Synergistic (1001) TMC-435 97.17 Synergistic (1013)

Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention. 

What is claimed is:
 1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 2. A compound of the structure

or a pharmaceutically acceptable salt thereof.
 3. A compound of the structure

or a pharmaceutically acceptable salt thereof.
 4. A compound of the structure

or a pharmaceutically acceptable salt thereof.
 5. A compound of the structure

or a pharmaceutically acceptable salt thereof.
 6. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 7. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 8. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 9. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing. 